Pyrrazolo-pyrimidine derivatives

ABSTRACT

The present invention relates to pyrrazolo-pyrimidine derivatives of formula (I): 
                         
wherein R 1  to R 4  and A are as defined in the specification, a process for the manufacture thereof, their use for treating or preventing metabotropic glutamate receptors mediated disorders, their use for the preparation of medicaments for treating such disorders and pharmaceutical compositions containing said derivatives.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of European Application No.05101027.0, filed Feb. 11, 2005, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor.

L-glutamic acid, the most commonly occurring neurotransmitter in theCNS, plays a critical role in a large number of physiological processes.The glutamate-dependent stimulus receptors are divided into two maingroups. The first main group forms ligand-controlled ion channels. Themetabotropic glutamate receptors (mGluR) form the second main group and,furthermore, belong to the family of G-protein-coupled receptors.

At present, eight different members of these mGluR are known and ofthese some even have sub-types. On the basis of structural parameters,the different influences on the synthesis of secondary metabolites andthe different affinity to low-molecular weight chemical compounds, theseeight receptors can be sub-divided into three sub-groups: mGluR1 andmGluR5 belong to group I, mGluR2 and mGluR3 belong to group II andmGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the group IIcan be used for the treatment or prevention of acute and/or chronicneurological disorders such as psychosis, schizophrenia, Alzheimer'sdisease, cognitive disorders and memory deficits. Other treatableindications in this connection are restricted brain function caused bybypass operations or transplants, poor blood supply to the brain, spinalcord injuries, head injuries, hypoxia caused by pregnancy, cardiacarrest and hypoglycaemia. Further treatable indications are chronic andacute pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS),dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficiency functions, such as e.g. musclespasms, convulsions, migraine, urinary incontinence, nicotine addiction,opiate addiction, anxiety, vomiting, dyskinesia, depressions and gliomasince mGluR2 antagonists have been found to reduce cell proliferation inhuman glioma cells (J. Neurochem. March 2003, 84(6): 1288-95).

SUMMARY OF THE INVENTION

The present invention provides pyrrazolo-pyrimidine derivatives offormula (I), a process for the manufacture thereof, their use fortreating or preventing metabotropic glutamate receptor mediateddisorders, pharmaceutical compositions containing them, and methods formanufacture of such compositions.

In particular, the present invention provides pyrrazolo-pyrimidinederivatives of the general formula (I):

wherein

-   A is selected from the group consisting of

-   R^(a) is H, halo or C₁₋₆-alkyl;-   R¹ is H, halo, C₁₋₆-alkoxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or    C₁₋₆-haloalkoxy;-   R² is halogen or C₁₋₆-haloalkyl;-   R³ is C₁₋₆-alkyl optionally substituted by hydroxy;

or is NR^(b)R^(c) wherein R^(b) and R^(c) are each independentlyselected from the group consisting of

-   H, C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms,    and C₁₋₆-alkyl which is optionally substituted by one or more    substituent(s) selected from the group consisting of halo, hydroxy,    C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and    —NR^(b)′R^(c)′, wherein R^(b′) and R^(c′) are each independently    selected from the group consisting of H and C₁₋₆-alkyl;-   or R^(b) and R^(c) can, together with the nitrogen atom to which    they are attached, form an optionally substituted heterocyclic group    having 5 to 12 ring atoms, wherein the substituents are selected    from the group consisting of halo, hydroxy, C₁₋₆-alkyl and    C₁₋₆-haloalkyl; and-   R⁴ is H, straight C₁₋₆-alkyl, C₁₋₆-haloalkyl or C₃₋₄-cycloalkyl;    and pharmaceutically acceptable salts thereof.

The invention includes all racemic mixtures, all their correspondingenantiomers and/or optical isomers. The compounds of formula (I) canalso be used in form of their prodrugs. Examples are esters, N-oxides,phosphate esters, glycoamide esters, glyceride conjugates and the like.The prodrugs can add to the value of the present compounds containingcompounds of the invention and a pharmaceutically acceptable carrier.The advantages in absorption, pharmacokinetics in distribution andtransport to the brain.

Compounds of formula I are metabotropic glutamate receptor antagonists.They can be used for the treatment or prevention of mGLuR5 receptormediated disorders, such as acute and/or chronic neurological disorders,in particular anxiety and chronic or acute pain selected from the groupconsisting of restricted brain function caused by bypass operations ortransplants, poor blood supply to the brain, spinal cord injuries, headinjuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia,chronic and acute pain, Huntington's chorea, amyotrophic lateralsclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy,idiopathic parkinsonism or parkinsonism caused by medicaments as well asglioma.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural forms unless the context clearly dictatesotherwise.

The term “alkyl” denotes a straight-chain or branched saturatedhydrocarbon residue with 1 to 6 carbon atoms, preferably with 1 to 4carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, i-butyl,t-butyl, and the like.

The term “alkoxy” denotes a lower alkyl residue as defined above boundvia an oxygen atom. Examples of “lower alkoxy” residues include methoxy,ethoxy, isopropoxy and the like.

The term “halogen” embraces fluorine, chlorine, bromine and iodine.

The terms “alkyl substituted by one or more halogen atoms” and“haloalkyl” each denotes an alkyl residue as defined above wherein atleast one hydrogen atom has been replaced with a halogen atom.

The terms “alkoxy substituted by one or more halogen atoms” and“haloalkoxy” each denotes an alkoxy residue as defined above wherein atleast one hydrogen atom has been replaced with a halogen atom. Examplesof lower alkoxy substituted by one or more halogen include2,2,2-trifluoroethoxy groups.

The term “alkenyl” used in the present description denotesstraight-chain or branched unsaturated hydrocarbon residues with 2-6,preferably 2-4 carbon atoms, such as ethenyl, 2-propenyl,isobutene-1-yl, and those specifically exemplified in the instant patentapplication.

The term “aryl” represents an aromatic carbocyclic group consisting ofone individual ring, or one or more fused rings in which at least onering is aromatic in nature. Preferred aryl groups are phenyl ornaphthyl.

The term “heteroaryl” refers to an aromatic group having 5 to 12 ringatoms and containing one or more heteroatoms selected from nitrogen,oxygen and sulphur. In a certain embodiment, the heteroaryl groupscontain one or more nitrogen atoms. Preferred heteroaryl groups have 5or 6 ring atoms. Examples of such heteroaryl groups are pyridinyl,pyrazinyl, pyrimidinyl or pyridazinyl.

The term “cycloalkyl” means a cycloalkyl group containing 3 to 12,preferably 3 to 8 and still more preferably 3 to 6, carbon atoms, suchas cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkylcontaining 3 to 4 carbon atoms are the most preferred.

The term “a heterocyclic group having 5 to 12 ring atoms” denotes aheterocyclic ring having 5 to 12, preferably 5 to 9 as still morepreferably 5 or 6, ring members containing at least one nitrogen atom asring members, and none, 1, 2 or 3 additional heteroatom ring membersselected from N, O and S, the remaining ring members being carbon atoms.Examples of 5 or 6 heterocyclic ring include but are not limited to1H-tetrazole; 2H-tetrazole; 1,2,3- and 1,24-triazole; imidazole;pyrrole; 1,2,3-, 1,3,4- or 1,2,5-thiadiazine; 1,4-oxazine; 1,2- or1,4-thiazine; 4-morpholinyl; 1-pyrrolidinyl; 1-piperazinyl, preferably4-morpholinyl; 1-pyrrolidinyl or 1-piperazinyl.

Substituents for such 5 or 6 membered heterocyclic ring include but arenot limited to halo, amino, nitro, cyano, hydroxy, C₁₋₆-alkyl optionallysubstituted by hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl, orCF₃, and preferably C₁₋₆-alkyl; or CF₃.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable addition salt” refers to any saltderived from an inorganic or organic acid or base.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The present invention provides pyrrazolo-pyrimidine derivatives of thegeneral formula (I):

wherein

-   A is selected from the group consisting of

-   R^(a) is H, halo or C₁₋₆-alkyl;-   R¹ is H, halo, C₁₋₆-alkoxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, or    C₁₋₆-haloalkoxy;-   R² is halogen or C₁₋₆-haloalkyl;-   R³ is C₁₋₆-alkyl optionally substituted by hydroxy;

or is NR^(b)R^(c) wherein R^(b) and R^(c) are each independentlyselected from the group consisting of

-   H, C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms,    and C₁₋₆-alkyl which is optionally substituted by one or more    substituent(s) selected from the group consisting of halo, hydroxy,    C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and    —NR^(b′)R^(c′), wherein R^(b′) and R^(c′) are each independently    selected from the group consisting of H and C₁₋₆-alkyl;-   or R^(b) and R^(c) can, together with the nitrogen atom to which    they are attached, form an optionally substituted heterocyclic group    having 5 to 12 ring atoms, wherein the substituents are selected    from the group consisting of halo, hydroxy, C₁₋₆-alkyl and    C₁₋₆-haloalkyl; and-   R⁴ is H, straight C₁₋₆-alkyl, C₁₋₆-haloalkyl or C₃₋₄-cycloalkyl;    and pharmaceutically acceptable salts thereof.

The invention includes all racemic mixtures, all their correspondingenantiomers and/or optical isomers. The compounds of formula (I) canalso be used in form of their prodrugs.

Examples are esters, N-oxides, phosphate esters, glycoamide esters,glyceride conjugates and the like. The prodrugs can add to the value ofthe present compounds containing compounds of the invention and apharmaceutically acceptable carrier. The advantages in absorption,pharmacokinetics in distribution and transport to the brain.

Preferred compounds of the invention are those compounds wherein:

-   A is selected from the group consisting of

-   R^(a) is H, halo, preferably Cl, or C₁₋₆-alkyl, preferably methyl;-   R¹ is H, halo, preferably Cl; C₁₋₆-alkoxy, preferably MeO or EtO;    C₁₋₆-alkyl, preferably methyl; C₁₋₆-haloalkyl, preferably CHF₂ or    CF₃; C₁₋₆-haloalkoxy, preferably CF₃CH₂O;-   R² is halogen, preferably Cl, or C₁₋₆-haloalkyl, preferably CF₃;-   R³ is NR^(b)R^(c) wherein R^(b) and R^(c) are each independently    selected from the group consisting of H, C₁₋₆-alkyl, preferably    methyl, ethyl, i-propyl, or t-butyl, each of which is optionally    substituted by one or more substituent(s) selected from the group    consisting of hydroxy and —NR^(b′c′), wherein R^(b′) and R^(c′) are    each independently selected from the group consisting of H and    C₁₋₆-alkyl, preferably methyl; and-   R⁴ is C₁₋₆-haloalkyl, preferably CHF₂ or CF₃, or C₃₋₄-cycloalkyl,    preferably cyclopropyl;    and pharmaceutically acceptable salts thereof.

More particularly, the invention provides compounds in which

-   A is selected from the group consisting of

-   R^(a) is H, Cl, or methyl;-   R¹ is H, Cl, MeO, EtO, methyl, CHF₂, CF₃, or CF₃CH₂O;-   R² is Cl, or CF₃;-   R³ is NR^(b)R^(c) wherein R^(b) and R^(c) are each independently    selected from the group consisting of H, methyl, ethyl, i-propyl, or    t-butyl, each of which is optionally substituted by one or more    substituent selected from the group consisting of hydroxy and    —NR^(b′c′), wherein R^(b′) and R^(c′) are each independently    selected from the group consisting of H and methyl; and-   R⁴ is CHF₂, CF₃, or cyclopropyl;    and pharmaceutically acceptable salts thereof.

Also encompassed by the compounds of formula (I) are those of formula(Ia):

wherein R^(a), R¹, R², R³ and R⁴ are as defined hereinabove for formula(I), and pharmaceutically acceptable salts thereof.

Examples of compounds of formula (Ia) include

-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;-   5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;-   5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;-   5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   5-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   5-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-2-chloro-thiophen-3-yl}-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-2-chloro-thiophen-3-yl}-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid [2-chloro-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid [2-chloro-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (2-methyl-5-sulfamoyl-thiophen-3-yl)-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (2-methyl-5-sulfamoyl-thiophen-3-yl)-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-2-methyl-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-2-methyl-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-dimethylamino-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-dimethylamino-ethylsulfamoyl)-thiophen-3-yl]-amide;-   5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid [2-chloro-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-amide;-   5-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid [5-(2-amino-ethylsulfamoyl)-2-chloro-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [(RS)-2-chloro-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-thiophen-3-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [(RS)-2-chloro-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    {2-chloro-5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-thiophen-3-yl}-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    {2-chloro-5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-thiophen-3-yl}-amide;    and-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid [5-(2-amino-ethylsulfamoyl)-2-chloro-thiophen-3-yl]-amide.

Also encompassed by the compounds of formula (I) are those of formula(Ib):

wherein R¹, R², R³ and R⁴ are as defined hereinabove for formula (I),and pharmaceutically acceptable salts thereof. Examples of compounds offormula (Ib) include

-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (5-sulfamoyl-[1,3,4]thiadiazol-2-yl)-amide; and-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (5-sulfamoyl-[1,3,4]thiadiazol-2-yl)-amide.

Also encompassed by the compounds of formula (I) are those of formula(Ic):

wherein R^(a), R¹, R², R³ and R⁴ are as defined hereinabove for formula(I), and pharmaceutically acceptable salts thereof. Examples ofcompounds of formula (Ic) include

-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;-   5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;-   5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;-   5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   5-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;-   5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;-   5-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;-   5-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   5-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [2-chloro-5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-thiophen-3-yl]-amide;-   7-Difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-4-methyl-thiazol-2-yl}-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-4-methyl-thiazol-2-yl}-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid [5-(2-hydroxy-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid [5-(2-hydroxy-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (5-sulfamoyl-thiazol-2-yl)-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid (5-sulfamoyl-thiazol-2-yl)-amide;-   5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-dimethylamino-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-dimethylamino-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiazol-2-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiazol-2-yl]-amide;-   5-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-amide;-   7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    {5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-4-methyl-thiazol-2-yl}-amide;-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    {5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-4-methyl-thiazol-2-yl}-amide;-   (RS)-7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [(RS)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-4-methyl-thiazol-2-yl]-amide;    and-   7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic    acid    [(RS)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-4-methyl-thiazol-2-yl]-amide.

Also encompassed by the compounds of formula (I) are those in which R³is C₁₋₆-alkyl optionally substituted by hydroxyl.

In another embodiment are encompassed compounds of formula (I) in whichR³ is NR^(b)R^(c) wherein R^(b) and R^(c) are independently selectedfrom the group consisting of: H, C₃₋₈-cycloalkyl, aryl, heteroarylhaving from 5 to 12 ring atoms, and C₁₋₆-alkyl which is optionallysubstituted by one or more substituent(s) selected from the groupconsisting of halo, hydroxy, C₃₋₈-cycloalkyl, aryl, heteroaryl havingfrom 5 to 12 ring atoms and —NR^(b′)R^(c′), wherein R^(b′) and R^(c′)are each independently selected from the group consisting of H andC₁₋₆-alkyl; or R^(b) and R^(c) can, together with the nitrogen atom towhich they are attached, form an optionally substituted heterocyclicgroup having 5 to 12 ring atoms, wherein the substituents are selectedfrom the group consisting of halo, hydroxy, C₁₋₆-alkyl andC₁₋₆-haloalkyl. Of these, compounds wherein R^(b) and R^(c) are hydrogenare preferred. Alternatively, preferred compounds in this embodiment arethose in which R^(b) and R^(c) are each independently C₁₋₆-alkyl,optionally substituted by one or more substituent(s) selected from thegroup consisting of halo, hydroxy, and C₃₋₈-cycloalkyl. As anotheralternative within this group are those compounds in which R^(b) andR^(c) are each independently C₁₋₆-alkyl, optionally substituted by—NR^(b′)R^(c′), wherein R^(b′) and R^(c′) are each independentlyselected from the group consisting of H and C₁₋₆-alkyl. As yet anotheralternative within this group are those compounds in which R^(b) andR^(c) together with the nitrogen atom to which they are attached, forman optionally substituted heterocyclic group having 5 to 12 ring atoms,wherein the substituents are selected from the group consisting of halo,hydroxy, C₁₋₆-alkyl and C₁₋₆-haloalkyl.

The compounds of the invention can be prepared according to a processcomprising reacting a compound of formula (VI):

with a compound of formula (VII):

wherein A, R¹, R², R³ and R⁴ are as defined in formula (I) above;to obtain the compound of formula (I), and if desired converting thecompound of formula (I) into its pharmaceutically acceptable additionsalt.

The pharmaceutically acceptable addition salts can be manufacturedreadily according to methods known per se and taking into considerationthe nature of the compound to be converted into a salt. Inorganic ororganic acids such as, for example, hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid, phosphoric acid or citric acid, formicacid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaricacid, methanesulphonic acid, p-toluenesulphonic acid and the like aresuitable for the formation of pharmaceutically acceptable salts of basiccompounds of formulae (I), (Ia), (Ib) and (Ic).

The synthesis of the intermediate compounds of formula (VI) above can becarried out in accordance with the following general procedure I whichprocedure is outlined below in scheme 1. As for the reaction of thecompound of formula (VII) with the compound of formula (VI), it can becarried out for example in accordance with the following generalprocedure II which procedure is outlined below in scheme 2. In theseschemes, A, R¹, R², R³ and R⁴ are as defined hereinabove. Procedures Iand II are applicable for the preparation of all the compounds accordingto formulae (I), (Ia), (Ib) and (Ic).

General Procedure IStep 1:

To a stirred solution of compound of formula (III) in an organic solvent(e.g. tert-butyl-methyl-ether) is added at room temperature a solutionof sodium methanolate in methanol followed by a solution of compound offormula (II) in an organic solvent (e.g. tert-butyl-methyl-ether). Thereaction mixture is stirred at room temperature for about 19 h, cooled,acidified and extracted (e.g. with diethyl ether). The combined organiclayers are washed and dried (e.g. MgSO₄) and evaporated to give crudethe compound of formula (IV) which can be used without furtherpurification.

Step 2:

A stirred mixture of commercially available3-amino-4-ethoxycarbonyl-pyrazole (compound of formula (V)) and compoundof formula (IV) in an organic acid (e.g. acetic acid) is heated underreflux conditions for about 1.5 h. The reaction mixture is evaporatedand the crude product is dissolved in a mixture of a concentrated base(e.g. KOH in methanol and water). The reaction mixture is stirred atabout 60° C. for about 1.5 h, cooled, acidified and concentrated. Theprecipitate is collected by filtration and further purified (e.g. bycrystallization from diethylether/methanol) to give the compound offormula (VI).

General Procedure IIStep 3:

To a stirred solution of compound of formula (VI) in a solvent (e.g.THF)is added at room temperature DMF, the solution is cooled to about 0° C.and oxalylchloride is added. The reaction mixture is stirred at roomtemperature for about 3 h and evaporated to dryness. The precipitate isdissolved in pyridine and, while stirring at room temperature,4-dimethylaminopyridine and a compound of formula (VII) are added. Thereaction mixture is allowed to stir at room temperature for about 16 h,evaporated to dryness and the crude product purified (e.g. by flashchromatography on silica gel) to yield the product, which can be furtherpurified (e.g. by crystallization from methanol/hexane).

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example compounds of formulaI and their pharmaceutically acceptable acid addition salts, and apharmaceutically acceptable carrier. Such pharmaceutical compositionscan be in the form of tablets, coated tablets, dragées, hard and softgelatine capsules, solutions, emulsions or suspensions. Thepharmaceutical compositions also can be in the form of suppositories orinjectable solutions.

The pharmaceutical compounds of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic and organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, glycerol,vegetable oil and the like. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

In addition, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula (I)or a pharmaceutically acceptable salt thereof and a therapeuticallyinert excipient are also an object of the present invention, as is aprocess for the production of such medicaments which comprises bringingone or more compounds of formula (I) or pharmaceutically acceptablesalts thereof and, if desired, one or more other therapeuticallyvaluable substances into a galenical dosage form together with one ormore therapeutically inert carriers.

The compounds of formula (I) and their pharmaceutically acceptable saltsare metabotropic glutamate receptor antagonists and can be used for thetreatment or prevention of acute and/or chronic neurological disorders,such as psychosis, schizophrenia, Alzheimer's disease, cognitivedisorders and memory deficits. Other treatable indications arerestricted brain function caused by bypass operations or transplants,poor blood supply to the brain, spinal cord injuries, head injuries,hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Furthertreatable indications are acute and chronic pain, Huntington's chorea,ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficient functions, such as e.g. muscle spasms,convulsions, migraine, urinary incontinence, nicotine addiction,psychoses, opiate addiction, anxiety, vomiting, dyskinesia, depressionand glioma.

The dosage at which the compounds of the invention can be administeredcan vary within wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, theeffective dosage for oral or parenteral administration is between0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred forall of the indications described. The daily dosage for an adult humanbeing weighing 70 kg accordingly lies between 0.7-1400 mg per day,preferably between 7 and 700 mg per day.

The compounds of the present invention are group II mGlu receptorantagonists. The compounds show activities, as measured in the assaydescribed below, of 0.150 μM or less, typically 0.030 μM or less, andideally of 0.010 μM or less. In the table below are described somespecific Ki values of representative compounds.

Ex. No. 2 3 8 35 K_(i) mGlu2 (μM) 0.0069 0.142 0.0025 0.027[³H]-LY354740 Binding on mGlu2 Transfected CHO Cell Membranes.Transfection and Cell Culture

cDNA encoding the rat mGlu2 receptor protein in pBluescript II wassubcloned into the eukaryotic expression vector pcDNA I-amp fromInvitrogen Ltd (Paisley, UK). This vector construct (pcD1mGR2) wasco-transfected with a psvNeo plasmid encoding the gene for neomycinresistance, into CHO cells by a modified calcium phosphate methoddescribed by Chen & Okayama (1988). The cells were maintained inDulbecco's Modified Eagle medium with reduced L-glutamine (2 mM finalconcentration) and 10% dialysed foetal calf serum from Gibco-Invitrogen(Carlsbad, Calif., USA). Selection was made in the presence of G-418(1000 ug/ml final) and MCPG??. Clones were identified by reversetranscription of 5 μg total RNA, followed by PCR mGlu2 receptor specificprimers 5′-atcactgcttgggtttctggcactg-3′ and5′-agcatcactgtgggtggcataggagc-3′in 60 mM Tris HCl (pH 10), 15 mM(NH4)₂SO₄, 2 mM MgCl₂, 25 units/ml Taq Polymerase with 30 cyclesannealing at 60° C. for 1 min., extention at 72° C. for 30 s, and 1 min.95° C. denaturation.

Membrane Preparation

Cells, cultured as above, were harvested and washed three times withcold PBS and frozen at −80° C. The pellet was resuspended in cold 20 mMHEPES-NaOH buffer containing 10 mM EDTA (pH 7.4), and homogenised with apolytron (Kinematica, AG, Littau, Switzerland) for 10 s at 10 000 rpm.After centrifugation for 30 min. at 4° C., the pellet was washed oncewith the same buffer, and once with cold 20 mM HEPES-NaOH buffercontaining 0.1 mM EDTA, (pH 7.4). Protein content was measured using themicro BCA method from Pierce-Perbio (Rockford, Ill., USA) using bovineserum albumin as standard.

[³H]-LY354740 Binding

After thawing, the membranes were resuspended in cold 50 mM Tris-HClbuffer containing 2 mM MgCl₂ (pH 7) (binding buffer). The finalconcentration of the membranes in the assays was 25 μg protein/ml.Inhibition experiments were performed with membranes incubated with 10nM [³H]-LY354740 at room temperature, for 1 hour, in presence of variousconcentrations of the compound to be tested. Following the incubations,membranes were filtered onto Whatmann GF/B glass fiber filters andwashed 5 times with cold binding buffer. Non specific binding wasmeasured in the presence of 10 μM DCG IV. After transfer of the filtersinto plastic vials containing 10 ml of Ultima-gold scintillation fluidfrom Perkin-Elmer(Boston, Mass., USA), the radioactivity was measured byliquid scintillation in a Tri-Carb 2500 TR counter (Packard, Zürich,Switzerland).

Data Analysis.

The inhibition curves were fitted with a four parameter logisticequation giving IC₅₀ values, and Hill coefficients.

EXAMPLES Synthesis of Starting Material

Almost all of the starting materials used in the general procedures Iand II are commercially available. The non-commercially availablestarting materials have been prepared according to the procedures asoutlined hereafter and unless otherwise specified, the intermediatecompounds described therein are novel compounds. Other startingmaterials useful in the general procedures I and II can be preparedtaking into account the following examples of preparation and usingknown methods.

A—Synthesis of Acetophenones Derivatives of Formula (II) Example A.14-Methyl-3-trifluoromethyl-acetophenone

To a stirred and cooled (0° C.) solution of potassium tert.-butanolate(1.39 g, 12 mmol) in DMSO (3 ml) was added diethyl malonate (1.9 ml, 12mmol) and the reaction mixture was stirred for 20 min at roomtemperature. To the white suspension was added at room temperature4-fluoro-3-trifluoromethyl-acetophenone (1 g, 5 mmol) and DMSO (2 ml).The reaction mixture was stirred for 6 h at 60° C. and for 16 h at roomtemperature. The reaction mixture was cooled (0° C.), a solution ofpotassium hydroxide (1.09 g, 19 mmol) in water (2 ml) was added and themixture was stirred at 100° C. for 23 h. The mixture was poured intoice/water (40 ml) and extracted with diethyl ether (2×40 ml). Thecombined organic layers were washed with water (3×30 ml), brine (30 ml),dried (MgSO₄) and evaporated. The crude product (0.92 g) was furtherpurified by column chromatography on silica gel (heptane/ethyl acetate3:1) to give the title compound (0.76 g, 77%) as a light yellow liquid.MS (EI) 202.0 [M].

Example A.2 4-Ethoxy-3-trifluoromethyl-acetophenone

To a stirred suspension of potassium ethanolate (2.36 g, 27 mmol) inethanol (30 ml) was added at room temperature a solution of4-fluoro-3-trifluoromethyl-acetophenone (2.5 g, 12 mmol) in ethanol (10ml). The reaction mixture was stirred at 60° C. for 2 h and evaporated.Ice/2 N HCl (50 ml) was added and the water layer was extracted withdiethylether (2×100 ml). The combined organic layers were washed withice-water (50 ml), brine (50 ml), dried (MgSO₄) and evaporated to givethe title compound (2.9 g, 98%) as a brown solid, which was used withoutfurther purification. MS (EI) 232.1 [M].

Example A.3 4-(2,2,2-Trifluoro-ethoxy)-3-trifluoromethyl-acetophenone

To a stirred solution of 4-fluoro-3-trifluoromethyl-acetophenone (2.5 g,12 mmol) in DMSO (15 ml) was added at room temperature2,2,2-trifluoroethanol (1.7 g, 17 mmol) and potassium hydroxide (1.74 g,27 mmol). The reaction mixture was stirred for 30 min at 40° C., ice/2NHCl (50 ml) was added and the water layer was extracted withdiethylether (2×100 ml). The combined organic layers were washed withice-water (50 ml), brine (50 ml), dried (MgSO₄) and evaporated to givethe title compound (3.6 g, 98%) as a brown solid, which was used withoutfurther purification. MS (EI) 286.1 [M].

Example A.4 3-Methyl-4-trifluoromethyl-acetophenone

The 1-(3-methyl-4-trifluoromethyl-phenyl)-ethanone was prepared by thefollowing sequence:

Step 1: 5-Methyl-2-nitro-4-trifluoromethyl-phenylamine

Under argon atmosphere, a suspension of potassium tert-butanolate (71.6g, 625 mmol) in DMSO (150 mL) was placed in a 1.5 L flask, fitted with amechanical stirrer. Then diethyl malonate (97.9 mL, 625 mmol) was addeddrop wise at 20-30° C. under ice bath cooling. To the thick whitesuspension was the added solid commercially available5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7](60.14 g, 250 mmol) in one portion, the mixture was diluted with DMSO(100 mL) and the red solution warmed up to 60° C. and stirred for 20 hat 60° C. The mixture was cooled to 23° C. and a solution of potassiumhydroxide (85%, 65.24 g, 1 mol) in water (100 mL) was added drop wise.The mixture was then heated to 100° C. and stirred for further 4 h. Themixture was cooled to 23° C., diluted with water (ca. 1000 mL),acidified with 37% HCl 3 to pH 3, and extracted three times withtert-butyl methyl ether (TBME) The organic layers were washed withbrine, dried over MgSO₄ and evaporated to give a brown solid, which wastriturated with hot heptane, filtered off and washed with heptane togive the title compound as a brown solid (50.0 g, 91%), which was usedwithout further purification. MS (ISN) 218.9 [M−H].

Step 2: 1-Bromo-5-methyl-2-nitro-4-trifluoromethyl-benzene

To a rapidly stirred mixture of tert-butyl nitrite (45.33 mL, 382 mmol)and copper(II) bromide (76.1 g, 341 mmol) in acetonitrile (450 mL) at65° C. was added cautiously solid5-methyl-2-nitro-4-trifluoromethyl-phenylamine from step 1 (50.0 g, 227mmol). After the addition was complete, stirring was continued forfurther 1 h at 65° C. The mixture was cooled to 23° C. and poured into 1N HCl (1000 mL), extracted twice with TBME, the organic layer was washedwith brine, dried over MgSO₄. Removal of the solvent in vacuum left abrown oil, which was purified by silica gel column chromatography withheptane/ethyl acetate 9:1 to give the title compound as a yellow liquid(49.8 g, 77%). MS (EI) 283.0 [M] and 285.0 [M⁺2].

Step 3: 5-Methyl-2-nitro-4-trifluoromethyl-benzonitrile

A mixture of 1-bromo-5-methyl-2-nitro-4-trifluoromethyl-benzene fromstep 2 (49.80 g, 175 mmol) and copper(I) cyanide (16.5 g, 184 mmol) in1-methyl-2-pyrrolidone (NMP) (180 mL) was heated up to 150° C. andstirred for 30 min under nitrogen atmosphere. The mixture was cooled to23° C. and poured into 1 N HCl, extracted with TBME, washed with brineand dried over Na₂SO₄. Removal of the solvent in vacuum left a brownoil, which was purified by silica gel column chromatography withheptane/ethyl acetate 4:1->2:1 to give the title compound as a lightyellow solid (35.48 g, 88%). MS (EI) 230.1 [M].

Step 4: 2-Amino-5-methyl-4-trifluoromethyl-benzonitrile

Iron powder (37.42 g, 670 mmol) was added in small portions to a stirredsuspension of finely grinded5-methyl-2-nitro-4-trifluoromethyl-benzonitrile from step 3 (34.58 g,150 mmol) in methanol (75 mL) and 37% HCl (93 mL). The internaltemperature was kept between 40 and 60° C. by external water bathcooling. The resulting brown solution was stirred for 1 h at 50° C.,giving a green suspension. The mixture was poured into ice cold water(600 mL), the precipitated solid was filtered off and washed with waterto give a green solid, which was dissolved in boiling ethanol (700 mL),activated carbon (ca. 10 g) was added and the mixture was refluxed for 1h. The hot solution was filtered and the solvent was evaporated invacuum to leave the title compound as a brown-yellow solid (23.55 g,78%), which was used without further purification. MS (EI) 200.1 [M].

Step 5: 3-Methyl-4-trifluoromethyl-benzonitrile

To a solution of 2-amino-5-methyl-4-trifluoromethyl-benzonitrile fromstep 4 (23.34 g, 117 mmol) in dry THF (350 mL) was added isoamyl nitrite(34.3 mL, 257 mmol) and the mixture was refluxed for 20 h. Additionalisoamyl nitrite (16.6 mL, 129 mmol) was added and the mixture wasrefluxed for further 20 h. The mixture was cooled to 23° C. and dilutedwith TBME, the organic layer was washed with 1 N HCl, sat. NaHCO₃-sol.and brine, dried over Na₂SO₄. Removal of the solvent in vacuum left abrown oil (25.82 g), which was purified by bulb to bulb distillation togive a yellow liquid (20.11 g), which was finally purified bydistillation to give the title compound as a yellow liquid (17.10 g,79%; bp 38-42° C. at 0.8 mbar). MS (EI) 185.1 [M].

Step 6: 3-Methyl-4-trifluoromethyl-benzoic acid

A mixture of 3-methyl-4-trifluoromethyl-benzonitrile from step 5 (16.25g, 88 mmol) and 3 N NaOH (88 mL, 264 mmol) in dioxane (90 mL) wasrefluxed for 18 h. The mixture was cooled to 23° C., diluted with TBME,acidified with 1 N HCl to pH 1 and extracted twice with TBME. Thecombined organic layers were washed with brine, dried over MgSO₄.Removal of the solvent in vacuum left the title compound as an off whitesolid (14.46 g, 81%), %), which was used without further purification.MS (ISN) 203.1 [M−H].

Step 7: N-Methoxy-3,N-dimethyl-4-trifluoromethyl-benzamide

To a suspension of 3-methyl-4-trifluoromethyl-benzoic acid from step 6(14.1 g, 69.1 mmol), N,O-dimethylhydroxylamine hydrochloride (10.78 g,111 mmol), N-methylmorpholine (12.14 mL, 111 mmol) and 4-DMAP (844 mg,691 mmol) in DCM (230 mL) at 0° C. were added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (15.98g, 82.9 mmol) and DMF (85 mL). The mixture was warmed up to 23° C. andwas stirred for 18 h under nitrogen atmosphere. The mixture was dilutedwith TBME, washed with water and twice brine, dried over Na₂SO₄. Removalof the solvent in vacuum left the title compound as a brown oil (16.92g, 99%), which was used without further purification. MS (ISP) 248.0[M⁺H].

Step 8: 1-(3-Methyl-4-trifluoromethyl-phenyl)-ethanone

To a solution of N-methoxy-3,N-dimethyl-4-trifluoromethyl-benzamide fromstep 7 (16.90 g, 68.36 mmol) in THF (280 mL) at −5° C. was added a 3 Mmethylmagnesium bromide solution in diethyl ether (45.6 mL, 136.7 mmol).The mixture was stirred at 0° C. for 1 h, then was warmed up to 23° C.and stirring was continued at 23° C. for further 1.5 h under nitrogenatmosphere. Then 1 N HCl (100 mL) was added drop wise to the mixture andstirring was continued for 30 min. The mixture was diluted with EtOAcand the aqueous layer was separated, the organic layer was washed withbrine and dried over MgSO₄. Removal of the solvent in vacuum left thetitle compound as a light brown liquid (12.87 g, 93.1%), which was usedwithout further purification. MS (EI) 202.1 [M].

Example A.5 3-Ethoxy-4-trifluoromethyl-acetophenone

The 1-(3-ethoxy-4-trifluoromethyl-phenyl)-ethanone was prepared by thefollowing sequence:

Step 1: 5-Ethoxy-2-nitro-4-trifluoromethyl-phenylamine

To EtOH (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol) andthe vigorous reaction had to be cooled with an ice bath. Stirring wascontinued until all potassium metal was dissolved. Solid commerciallyavailable 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No.35375-74-7] (57.74 g, 240 mmol) was added in one portion and theresulting dark red mixture was stirred at 55-60° C. for 4 days. The warmreaction mixture was slowly poured into H₂O (ca. 2000 mL), adjusted pHwith conc. HCl to pH 2, the yellow precipitate was filtered off, washedwith H₂O and dried in air at 60° C. to give a yellow solid (57.81 g,96%), which was used without further purification. MS (ISN) 249 [M⁻H].

Step 2: 1-Bromo-5-ethoxy-2-nitro-4-trifluoromethyl-benzene

Solid 5-ethoxy-2-nitro-4-trifluoromethyl-phenylamine from step 1 (57.81g, 231 mmol) was added slowly over 15 min to a rapidly stirred mixtureof tert-butyl nitrite (45.8 mL, 347 mmol) and anhydrous copper(II)bromide (77.4 g, 347 mmol) in acetonitrile (462 mL), which was heated to65° C. in an oil bath. Stirring at 65° C. was continued for 30 min, thereaction mixture was cooled to 23° C., poured into 1 N HCl, saturatedwith solid NaCl, extracted with TBME, dried over MgSO₄. Removal of thesolvent in vacuum left a dark brown oil (74.5 g). Silica gel columnchromatography with heptane/EtOAc 4:1 gave the title compound as ayellow solid (63.03 g, 87%). MS (EI) 313.0 [M] and 315.0 [M⁺2].

Step 3: 5-Ethoxy-2-nitro-4-trifluoromethyl-benzonitrile

A mixture of 1-bromo-5-ethoxy-2-nitro-4-trifluoromethyl-benzene fromstep 2 (61.81 g, 197 mmol) and CuCN (18.51 g, 207 mmol) in NMP (197 mL)was heated to 150° C. for 30 min. Cooled to 23° C., poured into 1 N HCl,extracted with TBME, washed with brine, dried over Na₂SO₄. Removal ofthe solvent in vacuum left a brown oil. Silica gel column chromatographywith heptane/EtOAc 4:1 gave the title compound as a yellow solid (46.73g, 91%). MS (EI) 260.1 [M].

Step 4: 2-Amino-5-ethoxy-4-trifluoromethyl-benzonitrile

Iron powder (40.96 g, 733 mmol) was added in small portions over 5 minto a stirred suspension of finely grinded5-ethoxy-2-nitro-4-trifluoromethyl-benzonitrile from step 3 (42.79 g,164.5 mmol) in MeOH (85 mL) and conc. HCl (102 mL) with water bathcooling keeping the internal temperature at 40-50° C. The resultingmixture was stirred for further 1 h at ca. 50° C. and then poured intoice cold H₂O (700 mL). The precipitate was filtered, washed with water,dried, and dissolved in boiling EtOH (800 mL), activated carbon (ca. 10g) was added, the mixture was refluxed for 45 min, the hot solution wasfiltered and evaporated to dryness to leave a yellow solid (31.81 g,84%), which was used without further purification. MS (EI) 230.1 [M].

Step 5: 3-Ethoxy-4-trifluoromethyl-benzonitrile

To a solution of 2-amino-5-ethoxy-4-trifluoromethyl-benzonitrile fromstep 4 (31.62 g, 137.4 mmol) in dry THF (410 mL) was added isoamylnitrite (40.4 mL, 302 mmol) and the mixture was refluxed for 16 h. Thesolvent was removed in vacuum to give an orange oil, which was dissolvedin sat. NaHCO₃-sol., extracted three times with diethyl ether. Thecombined organic layers were washed with 1 N HCl and brine, dried overNa₂SO₄. Removal of the solvent in vacuum left an orange oil, which waspurified by double Kugelrohr distillation (up to 160° C. bathtemperature at 1.5 mbar) to give the title compound as a light yellowsolid (25.06 g, 85%). MS (EI) 185.1 [M].

Step 6: 1-(3-Ethoxy-4-trifluoromethyl-phenyl)-ethanone

To a solution of 3-ethoxy-4-trifluoromethyl-benzonitrile from step 5(5.00 g, 23.2 mmol), copper(I) bromide (100 mg, 0.7 mmol),tert.-butyldimethylchlorosilane (4.20 g, 27.9 mmol) in dry THF (30 mL)at −70° C. was drop wise added a 3 M methylmagnesium bromide solution indiethyl ether (13.2 mL, 39.6 mmol). The mixture was stirred at −70° C.for 10 min, then was warmed up to 0° C. and stirring was continued at 0°C. for further 2 h under nitrogen atmosphere. Poured the reactionmixture onto ice and sat. NH₄Cl-sol., extracted three times with diethylether, washed the combined organic layers with brine, dried over MgSO₄.Removal of the solvent in vacuum left a brown oil, which was purified bysilica gel column chromatography with heptane/EtOAc 4:1 to give thetitle compound as a yellow liquid (1.84 g, 34%). MS (EI) 232 [M].

Example A.6 3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-acetophenone

The 1-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-ethanone wasprepared by the following sequence:

Step 1: 2-Nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenylamine

Commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine[CAS-No. 35375-74-7] (72.2 g, 300 mmol) was dissolved in DMSO (600 mL)and 2,2,2-trifluoroethanol (270 mL) were added at 23° C., the slightlyexothermic reaction was cooled with a ice bath. KOH (85%, 99.0 g, 1500mmol) were added slowly and the dark red reaction mixture was stirred at23° C. for 4 days. Transferred into a 3 L flask and 1500 ml H₂O wereadded under ice bath cooling, acidified with 3 N HCl and stirred at 23°C. for 3 h, filtered off the yellow precipitate, washed with H₂O anddried in air at 60° C. to give the title compound as a yellow solid(89.47 g, 98%). MS (ISN) 303.1 [M⁻H].

Step2:1-Bromo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzene

Solid 2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenylaminefrom step 1 (24.28 g, 80 mmol) was added slowly over 15 min to a rapidlystirred mixture of tert-butyl nitrite (14.23 mL, 120 mmol) and anhydrouscopper(II) bromide (26.75 g, 120 mmol) in acetonitrile (160 mL), whichwas heated to 65° C. in an oil bath. Stirring at 65° C. was continuedfor 2 h, the reaction mixture was cooled to 23° C., poured into 1 N HCl,saturated with solid NaCl, extracted with TBME, dried over MgSO₄.Removal of the solvent in vacuum left a dark brown oil (35.57 g). Silicagel column chromatography with heptane/EtOAc 4:1 gave the title compoundas an orange solid (30.54 g, 104%), which was used without furtherpurification. MS (EI) 367 [M] and 369 [M⁺2].

Step 3:2-Nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile

A mixture of1-bromo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzenefrom step 2 (30.54 g, 83.0 mmol) and CuCN (7.80 g, 87.1 mmol) in NMP (83mL) was heated to 150° C. for 30 min. Cooled to 23° C., poured into 1 NHCl, extracted with EtOAc, washed with brine, dried over Na₂SO₄. Removalof the solvent in vacuum left a dark brown oil (33.9 g). Silica gelcolumn chromatography with heptane/EtOAc 9:1->4:1 gave the titlecompound as a yellow solid (22.05 g, 85%). MS (EI) 314 [M].

Step 4:2-Amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile

Iron powder (15.80 g, 283.0 mmol) was added in small portions over 5 minto a stirred suspension of finely grinded2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile fromstep 3 (19.93 g, 63.4 mmol) in MeOH (32 mL) and conc. HCl (40 mL) withwater bath cooling keeping the internal temperature at 25-35° C. Theresulting mixture was stirred for further 1 h at ca. 30° C. and thenpoured into ice cold H₂O (400 mL). The precipitate was filtered, washedwith water, dried, and dissolved in boiling EtOH (400 mL), activatedcarbon (ca. 10 g) was added, the mixture was refluxed for 45 min, thehot solution was filtered and evaporated to dryness to leave a darkgreen solid (15.96 g, 84%), which was further purified by silica gelcolumn chromatography with heptane/EtOAc 4:1 to give the title compoundas a yellow solid (14.56 g, 81%). MS (ISN) 283 [M−H].

Step 5: 3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile

To a solution of2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile fromstep 4 (14.47 g, 50.9 mmol) in dry THF (153 mL) was added isoamylnitrite (15.0 mL, 112.0 mmol) and the mixture was refluxed for 20 h. Thesolvent was removed in vacuum to give an orange oil, which was dissolvedin TBME, washed with 1 N HCl, sat. NaHCO₃-sol. and brine, dried overNa₂SO₄. Removal of the solvent in vacuum left a brown solid (15.05 g),which was purified by Kugelrohr distillation (up to 155° C. bathtemperature at 1.2 mbar) to give the title compound as a light yellowsolid (10.83 g, 79%). MS (EI) 269 [M].

Step 6: 3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-benzoic acid

A mixture of 3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrilefrom step 5 (8.75 g, 33 mmol) and 3 M NaOH (3.9 g, 98 mmol in 33 mL H2O)in dioxane (33 mL) was refluxed for 7.5 h. Poured onto ice, acidifiedwith conc. HCl to pH 1, saturated with solid NaCl, extracted with TBME,dried over MgSO₄. Removal of the solvent in vacuum left the titlecompound as an off-white solid (9.22 g, 98%), %), which was used withoutfurther purification. MS (ISN) 286.9 [M−H].

Step 7:N-Methoxy-N-methyl-3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzamide

To a mixture of 3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzoicacid from step 6 (9.22 g, 32 mmol), N,O-dimethylhydroxylaminehydrochloride (5.00 g, 51 mmol), N-methylmorpholine (5.62 mL, 51 mmol)and 4-DMAP (391 mg, 3.2 mmol) in DCM (100 mL) and DMF (20 mL) at 0° C.was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC) (7.36 g, 38 mmol) and the mixture was stirred at 23° C. for 18 h.Poured onto ice cold 1 N HCl, extracted with TBME, washed with sat.NaHCO₃-sol. and brine, dried over Na₂SO₄. Removal of the solvent invacuum left the title compound as a brown oil (10.555 g, 100%), %),which was used without further purification. MS (EI) 331.0 [M].

Step 8: 1-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-ethanone

To a solution ofN-methoxy-N-methyl-3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzamidefrom step 7 (10.467 g, 32 mmol) in THF (100 mL) at −5° C. was addedmethylmagnesium bromide (3 M in Et₂O, 21.1 mL, 64 mmol). The mixture wasstirred at 0° C. for 15 min, then warmed up to 23° C., stirring wascontinued for further 1.5 h at 23° C. Cooled to 0° C., 1 N HCl (150 mL)was added dropwise, stirring was continued at 23° C. for 15 min, themixture was diluted with TBME, the phases were separated, the organiclayer was washed with water and brine, dried over MgSO4. Removal of thesolvent in vacuum left a yellow solid (9.021 g, 100%), which was usedwithout further purification. MS (EI) 286.1 [M].

B—Amide Derivatives of Formula (VII) Example B.14-Amino-5-chloro-thiophene-2-sulfonic acid amide

Hydrogenation of a stirred solution of5-chloro-4-nitro-thiophene-2-sulfonamide [CAS-No. 61714-46-3;commercially available] (1.13 g, 4.66 mmol) in methanol (140 ml) onRaney-Nickel (1.13 g) for 3 h at room temperature yielded after removalof the catalyst by filtration, evaporation and column chromatography onsilica gel (ethyl acetate/hexane) the title compound as a light brownsolid. MS (ISP) 211.0 [(M−H)⁻], mp 138° C.

Example B.2 4-Amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide

a) To a stirred solution of 2-amino-2-methyl-1-propanol (0.75 g, 8.39mmol) in dioxane (21 ml) was added at room temperature5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.0 g, 7.63 mmol) andtriethylamine (1.17 ml, 8.39 mmol). The light yellow suspension wasstirred at room temperature for 17 h, poured into water (100 ml) andextracted with dichloromethane (3×75 ml). The combined organic layerswere washed with water (100 ml) and brine (70 ml), dried (MgSO₄) andevaporated. The crude product was further purified by columnchromatography on silica gel (heptane/ethyl acetate 1:1) and subsequentcrystallization from ethyl acetate/hexane to yield5-chloro-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (0.73 g, 30%) as a light brownsolid. MS (ISP) 313.1 [(M−H)⁻], mp 136° C.

b) Hydrogenation of a stirred solution of5-chloro-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (0.66 g, 2.1 mmol) in methanol (70ml) on Raney-Nickel (0.66 g) for 3 h at room temperature yielded afterremoval of the catalyst by filtration, evaporation and purification ofthe crude product by column chromatography on silica gel (ethylacetate/hexane) followed by crystallization from ethyl acetate/hexanethe title compound (0.41 g, 69%) as a light brown solid. MS (ISP) 282.8[(M−H)⁻], mp 113° C.

Example B.3 2-Amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide

a) To a stirred solution of 2-amino-2-methyl-1-propanol (1.14 g, 13mmol) in dioxane (20 ml) was added at 0° C. (ice water bath)commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride(2.95 g, 12 mmol) and triethylamine (1.78 ml, 13 mmol). The light yellowsuspension was stirred at room temperature for 17 h, poured into water(100 ml) and extracted with dichloromethane (2×10 ml). The combinedorganic layers were washed with sat. NaHCO₃ solution (2×70 ml) and brine(70 ml), dried (MgSO₄) and evaporated. The crude product was furtherpurified by column chromatography on silica gel (ethyl acetate/MeOH 9:1)and subsequent crystallization (ethyl acetate/MeOH/heptane) to yield2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (1.15 g, 32%) as a light brownsolid. MS (ISP) 306.1 [(M−H)⁻]; mp 194° C.

b) A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (1.15 g, 3.58 mmol) in 6Nhydrochloric acid (14 ml) was heated for 2 h at 80° C., evaporated., andsaturated NaHCO₃ solution (30 ml) was added. The mixture was extractedwith ethyl acetate (3×50 ml), the combined organic layers washed withbrine (30 ml), dried (MgSO₄) and evaporated. The crude product wasfurther purified by column chromatography on silica gel(dichloromethane/MeOH/NH₄OH 80:10:1) to yield the title compound (0.68g, 71%) as a white solid. MS (ISP) 264.0 [(M−H)⁻]; mp 146° C.

Example B.4 4-Amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide

a) To a stirred solution of 2-amino-1,3-propanediol (0.5 g, 5.49 mmol)in water (2 ml) was added at room temperature magnesium oxide (1.11 g,27.5 mmol) and THF (6 ml). The suspension was stirred at roomtemperature for 30 min and a solution of5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.88 g, 10.9 mmol) in THF(2 ml) was added. The light yellow suspension was stirred at roomtemperature for 1 h and, after filtration on Dicalit, evaporated. Water(60 ml) was added and the mixture was extracted with ethyl acetate (3×50ml). The combined organic layers were washed with brine (70 ml), dried(MgSO₄) and evaporated. The crude product was further purified by columnchromatography on silica gel (heptane/ethyl acetate 1:1) and subsequentcrystallization from ethyl acetate/hexane to yield5-chloro-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide (0.76 g, 44%) as a light yellowsolid. MS (ISP) 314.9 [(M−H)⁻], mp 142° C.

b) Hydrogenation of a stirred solution of5-chloro-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide (0.67 g, 2.12 mmol) in methanol(67 ml) on Raney-Nickel (0.67 g) for 2.5 h at room temperature yieldedafter removal of the catalyst by filtration, evaporation andpurification of the crude product by column chromatography on silica gel(dichloromethane/MeOH) followed by crystallization from ethylacetate/hexane the title compound (0.47 g, 77%) as a light brown solid.MS (ISP) 286.8 [(M+H)⁺], mp 132° C.

Example B.5 4-Amino-5-chloro-thiophene-2-sulfonic acidbis-(2-hydroxy-ethyl)-amide

a) To a stirred solution of diethanolamine (1.16 g, 11 mmol) in water (4ml) was added at room temperature magnesium oxide (2.22 g, 55 mmol) andTHF (16 ml). The suspension was stirred at room temperature for 30 minand a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (3.46 g,13.2 mmol) in THF (4 ml) was added. The light yellow suspension wasstirred at room temperature for 1 h and, after filtration on Dicalit,evaporated. Water (60 ml) was added and the mixture was extracted withethyl acetate (3×50 ml). The combined organic layers were washed withbrine (70 ml), dried (MgSO₄) and evaporated. The crude product wasfurther purified by flash chromatography on silica gel (heptane/ethylacetate) to yield 5-chloro-4-nitro-thiophene-2-sulfonic acidbis-(2-hydroxy-ethyl)-amide (0.48 g, 13%) as a yellow solid. MS (ISP)331.2 [(M+H)⁺], mp 113° C.

b) Hydrogenation of a stirred solution of5-chloro-4-nitro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide(0.40 g, 1.21 mmol) in methanol (40 ml) on Raney-Nickel (0.40 g) for 4 hat room temperature yielded after removal of the catalyst by filtration,evaporation and purification of the crude product by flashchromatography on silica gel (dichloromethane/MeOH) the title compound(0.19 g, 52%) as a yellow solid. MS (ISP) 301.0 [(M+H)⁺], mp 96° C.

Example B.6 4-Amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-ethyl)-amide

a) To a stirred solution of ethanolamine (0.67 g, 11 mmol) in water (4ml) was added at room temperature magnesium oxide (2.22 g, 55 mmol) andTHF (12 ml). The suspension was stirred at room temperature for 30 minand a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (3.46 g,13.2 mmol) in THF (4 ml) was added. The light yellow suspension wasstirred at room temperature for 1 h and, after filtration on Dicalit,evaporated. Water (60 ml) was added and the mixture was extracted withethyl acetate (3×50 ml). The combined organic layers were washed withbrine (70 ml), dried (MgSO₄) and evaporated. The crude product wasfurther purified by flash chromatography on silica gel (heptane/ethylacetate) and subsequent crystallization from ethyl acetate/hexane toyield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide(1.39 g, 44%) as a yellow solid. MS (ISP) 284.8 [(M−H)⁻], mp 99° C.

b) Hydrogenation of a stirred solution of5-chloro-4-nitro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide(1.28 g, 4.46 mmol) in methanol (120 ml) on Raney-Nickel (1.28 g) for 4h at room temperature yielded after removal of the catalyst byfiltration, evaporation and purification of the crude product by flashchromatography on silica gel (dichloromethane/MeOH) the title compound(0.78 g, 68%) as a yellow solid. MS (ISP) 254.9 [(M−H)⁻], mp 100° C.

Example B.7 4-Amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide

a) To a stirred solution of 2-amino-2-methyl-1,3-propanediol (0.44 g,4.2 mmol) in THF (10 ml) was added at room temperature5-chloro-4-nitrothiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) andtriethylamine (0.58 ml, 4.2 mmol). The light yellow suspension wasstirred at room temperature for 17 h, poured into water (100 ml) andextracted with dichloromethane (3×75 ml). The combined organic layerswere washed with water (100 ml) and brine (70 ml), dried (MgSO₄) andevaporated. The crude product was further purified by flashchromatography on silica gel (heptane/ethyl acetate) and subsequentcrystallization from ethyl acetate/hexane to yield5-chloro-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (0.25 g, 20%) as alight brown solid. Mp 133° C.

b) Hydrogenation of a stirred solution of5-chloro-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (0.25 g, 0.76 mmol) inmethanol (30 ml) on Raney-Nickel (0.26 g) for 5 h at room temperatureyielded after removal of the catalyst by filtration, evaporation andpurification of the crude product by flash chromatography on silica gel(ethyl acetate/heptane) followed by crystallization from ethylacetate/hexane the title compound (0.16 g, 68%) as a light brown solid.MS (ISP) 299.1 [(M−H)⁻], mp 136° C.

Example B.8 2-Amino-4-methyl-thiazole-5-sulfonic acidbis-(2-hydroxy-ethyl)-amide

a) To a stirred solution of diethanolamine (1.24 g, 11.8 mmol) indioxane (20 ml) was added at 0° C. (ice water bath) commerciallyavailable 2-acetamido-4-methyl-thiazole-5-sulfonyl chloride (1.0 g, 3.93mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspensionwas stirred at room temperature for 17 h, and evaporated. The crudeproduct was further purified by flash chromatography on silica gel(dichloromethane/MeOH) and subsequent crystallization(dichloromethane/MeOH/hexane) to yield2-acetamido-4-methyl-thiazole-5-sulfonic acidbis-(2-hydroxy-ethyl)-amide (0.74 g, 58%) as a white solid. MS (ISP)324.0 [(M+H)⁺]; mp 204° C.

b) A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acidbis-(2-hydroxy-ethyl)-amide (0.7 g, 2.16 mmol) in 6N hydrochloric acid(8 ml) was heated for 2 h at 80° C., evaporated., and saturated NaHCO₃solution (50 ml) was added. The mixture was extracted with ethyl acetate(3×50 ml), the combined organic layers washed with brine (30 ml) anddried (MgSO₄). The crude product was further purified by crystallization(hexane) to yield the title compound (0.45 g, 74%) as a white solid. MS(ISP) 281.9 [(M+H)⁺]; mp 141° C.

Example B.9 2-Amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide

a) To a stirred solution of 2-amino-2-methyl-1,3-propanediol (1.86 g,17.7 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath)commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride(1.5 g, 5.89 mmol) and triethylamine (0.9 ml, 6 mmol). The light yellowsuspension was stirred at room temperature for 17 h, and evaporated. Thecrude product was further purified by flash chromatography on silica gel(ethyl acetate/MeOH) and subsequent crystallization(dichloromethane/MeOH/hexane) to yield2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (0.33 g, 17%) as awhite solid. MS (ISP) 322.2 [(M−H)⁻]; mp 201° C.

b) A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (0.33 g, 1.02 mmol) in6N hydrochloric acid (4 ml) was heated for 2 h at 80° C., evaporated.,and saturated NaHCO₃ solution (30 ml) was added. The mixture wasextracted with ethyl acetate (3×50 ml), the combined organic layerswashed with brine (30 ml) and dried (MgSO₄). The crude product wasfurther purified by crystallization (dichloromethane/MeOH/hexane) toyield the title compound (0.11 g, 38%) as a white solid. MS (ISP) 280.0[(M−H)⁻]; mp 170° C.

Example B.10 2-Amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-ethyl)-amide

a) To a stirred solution of ethanolamine (1.08 g, 17.7 mmol) in dioxane(20 ml) was added at 0° C. (ice water bath) commercially available2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.5 g, 5.89 mmol) andtriethylamine (0.9 ml, 6 mmol). The light yellow suspension was stirredat room temperature for 17 h, and evaporated. The crude product wasfurther purified by flash chromatography on silica gel (ethylacetate/MeOH) and subsequent crystallization(dichloromethane/MeOH/hexane) to yield2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-amide(1.0 g, 61%) as a white solid. MS (ISP) 278.0 [(M−H)⁻]; mp 211° C.

b) A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-ethyl)-amide (0.95 g, 3.4 mmol) in 6N hydrochloric acid (13ml) was heated for 2 h at 80° C., evaporated, and saturated NaHCO₃solution (20 ml) was added. The mixture was extracted with ethyl acetate(3×50 ml), the combined organic layers washed with brine (50 ml) anddried (MgSO₄). The crude product was further purified by crystallization(dichloromethane/MeOH/hexane) to yield the title compound (0.51 g, 63%)as a white solid. MS (ISP) 236.0 [(M−H)⁻]; mp 151° C.

Example B.11 4-Amino-5-methyl-thiophene-2-sulfonic acid amide

a) To a stirred solution of 5-methyl-4-nitrothiophene-2-sulfonylchloride [CAS No. 61714-77-0] (1.0 g, 4.14 mmol) in THF (20 ml) wasadded at 0° C. (ice water bath) ammonium hydroxide solution (25%, 5 ml).The reaction mixture was stirred at room temperature for 1 h,evaporated, poured into water (30 ml) and extracted with ethyl acetate(2×50 ml). The combined organic layers were washed with brine (2×30 ml),dried (MgSO₄) and evaporated. The crude product was further purified bycrystallization from ethyl acetate/hexane to yield5-methyl-4-nitro-thiophene-2-sulfonamide (0.75 g, 82%) as a brown solid.MS (ISP) 221.0 [(M−H)⁻], mp 120° C.

b) Hydrogenation of a stirred solution of5-methyl-4-nitro-thiophene-2-sulfonamide (0.50 g, 2.25 mmol) in methanol(15 ml) on Raney-Nickel (0.5 g) for 16 h at room temperature yieldedafter removal of the catalyst by filtration, evaporation andcrystallization (methanol/diethyl ether/hexane) the title compound as alight brown solid. MS (ISP) 191.0 [(M−H)⁻], mp 175° C.

Example B.12 4-Amino-5-methyl-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide

a) To a stirred solution of 2-amino-2-methyl-1-propanol (1.11 g, 12.4mmol) in dioxane (20 ml) was added at 0° C. (ice water bath)5-methyl-4-nitrothiophene-2-sulfonyl chloride [CAS No. 61714-77-0] andtriethylamine (0.63 ml, 4.56 mmol). The light yellow suspension wasstirred at room temperature for 17 h, and evaporated. The crude productwas further purified by column chromatography on silica gel (ethylacetate/MeOH) and subsequent crystallization (ethyl acetate/heptane) toyield 5-methyl-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (0.71 g, 58%) as a light brownsolid. MS (ISP) 293.0 [(M−H)⁻]; mp 126° C.

b) Hydrogenation of a stirred solution of5-methyl-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (0.60 g, 2.04 mmol) in methanol (20ml) on Raney-Nickel (0.6 g) for 7 h at room temperature yielded afterremoval of the catalyst by filtration, evaporation and crystallization(diethyl ether/hexane) the title compound as an off-white solid. MS(ISP) 262.9 [(M−H)⁻], mp 118° C.

Example B.13 2-Amino-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide

a) To a stirred solution of 2-amino-2-methyl-1-propanol (1.11 g, 12.5mmol) in dioxane (20 ml) was added at 0° C. (ice water bath)2-acetamido-thiazole-5-sulfonyl chloride [CAS No. 69812-30-2;commercially available] (1.0 g, 4.15 mmol) and triethylamine (0.64 ml,4.57 mmol). The light yellow suspension was stirred at room temperaturefor 17 h, and evaporated. The crude product was further purified bycolumn chromatography on silica gel (ethyl acetate) to yield2-acetamido-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (0.72 g, 59%) as a white solid. MS(ISP) 292.1 [(M−H)⁻]; mp 206° C.

b) A stirred suspension of 2-acetamido-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (0.68 g, 2.32 mmol) in 6Nhydrochloric acid (20 ml) was heated for 2 h at 80° C., evaporated., andsaturated NaHCO₃ solution (30 ml) was added. The mixture was extractedwith ethyl acetate (3×50 ml), the combined organic layers washed withbrine (30 ml), dried (MgSO₄) and evaporated. The crude product wasfurther purified by column chromatography on silica gel(dichloromethane/MeOH/NH₄OH 80:10:1) to yield the title compound (0.42g, 72%) as a colorless oil. MS (ISP) 250.0 [(M−H)⁻].

Example B.14 4-Amino-5-chloro-thiophene-2-sulfonic acid(2-dimethylamino-ethyl)-amide

a) To a stirred solution of N,N-dimethylethylenediamine (0.67 g, 7.6mmol) in dioxane (25 ml) was added at room temperature5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.0 g, 7.64 mmol) andtriethylamine (1.17 ml, 8.4 mmol). The light yellow suspension wasstirred at room temperature for 17 h, and evaporated. The crude productwas further purified by flash chromatography on silica gel(dichloromethane/methanol), and subsequent crystallization from ethylacetate to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid(2-dimethylamino-ethyl)-amide (1.16 g, 48%) as a light brown solid. MS(ISP) 312.0 [(M−H)⁻], mp 178° C.

b) Hydrogenation of a stirred solution of5-chloro-4-nitro-thiophene-2-sulfonic acidbis-(2-dimethylamino-ethyl)-amide (1.09 g, 3.47 mmol) in methanol (100ml) and tetrahydrofurane (30 ml) on Raney-Nickel (1.1 g) for 5 h at roomtemperature yielded after removal of the catalyst by filtration,evaporation and purification of the crude product by crystallization(ethyl acetate/MeOH) the title compound (0.64 g, 65%) as a brown solid.MS (ISP) 282.0 [(M−H)⁻], mp 184° C.

Example B.15 2-Amino-4-methyl-thiazole-5-sulfonic acid(2-dimethylamino-ethyl)-amide

a) To a stirred solution of N,N-dimethylethylenediamine (1.04 g, 11.8mmol) in tetrahydrofurane (14 ml) was added at 0° C. (ice water bath)commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride(1.0 g, 3.93 mmol) and triethylamine (0.6 ml, 4 mmol). The light yellowsuspension was stirred at room temperature for 17 h, and evaporated. Thecrude product was further purified by column chromatography on silicagel (dichloromethane/MeOH/NH₄OH 80:10:1) and subsequent crystallization(dichloromethane/hexane) to yield2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-dimethylamino-ethyl)-amide (1.07 g, 89%) as a white solid. MS (ISP)305.1 [(M−H)⁻]; mp 143° C.

b) A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-dimethylamino-ethyl)-amide (1.0 g, 3.26 mmol) in 6N hydrochloric acid(13 ml) was heated for 2 h at 80° C., and 2N NaHCO₃ solution (100 ml)was added. The mixture was extracted with ethyl acetate (3×50 ml), thecombined organic layers washed with brine (50 ml) and dried (MgSO₄). Thecrude product was further purified by crystallization (ethyl aceate) toyield the title compound (0.68 g, 79%) as a white solid. MS (ISP) 262.9[(M−H)⁻]; mp 153° C.

Example B.16 2-Amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide

a) To a stirred solution of 2-amino-1,3-propanediol (2.15 g, 23.6 mmol)in THF (26 ml) was added at 0° C. (ice water bath) commerciallyavailable 2-acetamido-4-methylthiazole-5-sulfonyl chloride (2.0 g, 7.85mmol) and triethylamine (1.2 ml, 8.64 mmol). The light yellow suspensionwas stirred at room temperature for 17 h, and evaporated. The crudeproduct was further purified by column chromatography on silica gel(dichloromethane/MeOH/NH₄OH 80:10:1) to yield2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide (1.46 g, 60%) as a light yellowsolid. MS (ISP) 308.1 [(M−H)⁻]; mp 217° C.

b) A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide (1.45 g, 4.69 mmol) in 6Nhydrochloric acid (22 ml) was heated for 2 h at 80° C., evaporated, andsaturated NaHCO₃ solution (50 ml) was added. The mixture was extractedwith ethyl acetate (3×50 ml), the combined organic layers washed withbrine (50 ml), dried (MgSO₄) and evaporated. The crude product wasfurther purified by crystallization (dichloromethane/MeOH/hexane) toyield the title compound (0.55 g, 44%) as an off-white solid. MS (ISP)266.0 [(M−H)⁻].

Example B.17[2-(4-Amino-5-chloro-thiophene-2-sulfonylamino)-ethyl]-carbamic acidtert-butyl ester

a) To a stirred solution of tert-butyl N-(2-aminoethyl)-carbamate (0.46g, 2.87 mmol) in THF (6 ml) was added at 0° C. (ice water bath)5-chloro-4-nitrothiophene-2-sulfonyl chloride (0.5 g, 1.91 mmol) andtriethylamine (0.29 ml, 2.1 mmol). The light yellow suspension wasstirred at room temperature for 17 h, and evaporated. The crude productwas further purified by flash chromatography on silica gel (ethylacetate/heptane), and subsequent crystallization from ethylacetate/hexane to yield[2-(5-chloro-4-nitro-thiophene-2-sulfonylamino)-ethyl]-carbamic acidtert-butyl ester (0.53 g, 72%) as a light yellow solid. MS (ISP) 384.1[(M−H)⁻], mp 147° C.

b) Hydrogenation of a stirred solution of[2-(5-chloro-4-nitro-thiophene-2-sulfonylamino)-ethyl]-carbamic acidtert-butyl ester (0.47 g, 1.22 mmol) in methanol (40 ml) on Raney-Nickel(0.47 g) for 5 h at room temperature yielded after removal of thecatalyst by filtration, evaporation and purification of the crudeproduct by crystallization (dichloromethane/MeOH) the title compound(0.38 g, 88%) as a light brown solid. MS (ISP) 354.1 [(M−H)⁻], mp 116°C.

Example B.18(RS)-1-(4-Amino-5-chloro-thiophene-2-sulfonyl)-pyrrolidin-3-ol

a) To a stirred solution of (RS)-3-pyrrolidinol (0.75 g, 8.6 mmol) inTHF (18 ml) was added at room temperature5-chloro-4-nitrothiophene-2-sulfonyl chloride (1.5 g, 5.72 mmol) andtriethylamine (0.88 ml, 6.3 mmol). The light yellow suspension wasstirred at room temperature for 17 h, and evaporated. The crude productwas further purified by column chromatography on silica gel (ethylacetate), and subsequent crystallization fromdichloromethane/MeOH/hexane to yield(RS)-1-(5-chloro-4-nitro-thiophene-2-sulfonyl)-pyrrolidin-3-ol (0.65 g,36%) as a yellow solid. MS (EI) 312.0 [(M)⁺], mp 96° C.

b) Hydrogenation of a stirred solution of(RS)-1-(5-chloro-4-nitro-thiophene-2-sulfonyl)-pyrrolidin-3-ol (0.92 g,2.94 mmol) in methanol (90 ml) on Raney-Nickel (0.92 g) for 7 h at roomtemperature yielded after removal of the catalyst by filtration,evaporation and purification of the crude product by flashchromatography (ethyl acetate/heptane) and subsequent crystallization(dichloromethane/MeOH/hexane) the title compound (0.30 g, 36%) as ayellow solid. MS (EI) 282.0 [(M)⁺], mp 156° C.

Example B.194-Methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine

a) To a stirred solution of 1-methylpiperazine (1.18 g, 11.8 mmol) inTHF (24 ml) was added at 0° C. (ice water bath) commercially available2-acetamido-4-methylthiazole-5-sulfonyl chloride (2.0 g, 7.85 mmol) andtriethylamine (1.2 ml, 8.6 mmol). The light yellow suspension wasstirred at room temperature for 17 h, and evaporated. The crude productwas further purified by column chromatography on silica gel(dichloromethane/MeOH 9:1) and subsequent crystallization(dichloromethane/MeOH/hexane) to yield2-acetamido-4-methyl-thiazole-5-sulfonic acid(4-methylpiperazinyl)-amide (1.85 g, 74%) as a white solid. MS (ISP)319.0 [(M+H)⁺]; mp 245° C.

b) A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid(4-methylpiperazinyl)-amide (1.73 g, 5.43 mmol) in 6N hydrochloric acid(22 ml) was heated for 2 h at 80° C., evaporated, and saturated NaHCO₃solution (75 ml) was added. The mixture was extracted with ethyl acetate(3×50 ml), the combined organic layers washed with brine (50 ml), dried(MgSO₄) and evapoarted. The crude product was further purified bycrystallization (ethyl acetate/MeOH/hexane) to yield the title compound(1.14 g, 76%) as a white solid. MS (ISP) 277.0 [(M+H)⁺]; mp 188° C.

Example B.20 2-Amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-ethyl)-methyl-amide

a) To a stirred solution of 2-(methylamino)-ethanol (0.44 g, 5.86 mmol)in THF (12 ml) was added at 0° C. (ice water bath) commerciallyavailable 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.0 g, 3.92mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspensionwas stirred at room temperature for 17 h, and evaporated. The crudeproduct was further purified by flash chromatography on silica gel(dichloromethane/MeOH) and subsequent crystallization(dichloromethane/MeOH/hexane) to yield2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-ethyl)-methyl-amide (0.93 g, 81%) as a white solid. MS (ISP)294.0 [(M+H)⁺]; mp 189° C.

b) A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-ethyl)-methyl-amide (0.85 g,2.9 mmol) in 6N hydrochloric acid(13 ml) was heated for 2 h at 80° C., evaporated, and saturated NaHCO₃solution (50 ml) was added. The mixture was extracted with ethyl acetate(3×50 ml), the combined organic layers washed with brine (50 ml), dried(MgSO₄) and evaporated. The crude product was further purified bycrystallization (dichloromethane/MeOH/hexane) to yield the titlecompound (0.49 g, 67%) as a white solid. MS (EI) 251.1 [(M)⁺]; mp 118°C.

Example B.21 4-Amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-ethyl)-methyl-amide

a) A suspension of 2-(methylamino)-ethanol (0.29 g, 3.86 mmol) andmagnesium oxide (0.77 g, 19.1 mmol) in THF (4 ml) and water (1.4 ml) wasallowed to stir at room temperature for 30 min,5-chloro-4-nitrothiophene-2-sulfonyl chloride (1.0 g, 3.81 mmol)dissolved in THF (1.6 ml) was added drop wise at room temperature over aperiod of 1 h and the reaction mixture was allowed to stir for anadditional hour. Filtration over Decalite and evaporation yielded thecrude product which was further purified by flash chromatography onsilica gel (ethyl acetate/heptane) to yield5-chloro-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-ethyl)-methyl-amide (0.4 g, 35%) as a yellow solid. MS (EI)300.0 [(M)⁺], mp 62° C.

b) Hydrogenation of a stirred solution of5-chloro-4-nitro-thiophene-2-sulfonic acid(2-hydroxy-ethyl)-methyl-amide (0.58 g, 1.93 mmol) in methanol (50 ml)on Raney-Nickel (0.58 g) for 6 h at room temperature yielded afterremoval of the catalyst by filtration, evaporation and purification ofthe crude product by flash chromatography (dichloromethane/MeOH) thetitle compound (0.15 g, 29%) as a yellow oil. MS (ISP) 270.9 [(M+H)⁺].

Example B.222-Chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-ylamine

a) A suspension of 1-methyl-piperazine (0.38 g, 3.79 mmol) and magnesiumoxide (0.38 g, 9.43 mmol) in THF (2.1 ml) and water (0.7 ml) was allowedto stir at room temperature for 30 min,5-chloro-4-nitrothiophene-2-sulfonyl chloride (0.5 g, 1.91 mmol)dissolved in THF (0.7 ml) was added drop wise at room temperature over aperiod of 1 h and the reaction mixture was allowed to stir for anadditional hour. Filtration over Decalite and evaporation yielded thecrude product which was further purified by flash chromatography onsilica gel (dichloromethane/MeOH) to yield5-chloro-4-nitro-thiophene-2-sulfonic acid (4-methyl-piperazinyl)-amide(0.14 g, 23%) as a yellow solid. MS (ISP) 326.3 [(M+H)⁺], mp 180° C.

b) Hydrogenation of a stirred solution of5-chloro-4-nitro-thiophene-2-sulfonic acid (4-methyl-piperazinyl)-amide(0.39 g, 1.2 mmol) in methanol (40 ml) on Raney-Nickel (0.39 g) for 4 hat room temperature yielded after removal of the catalyst by filtration,evaporation and purification of the crude product by flashchromatography (dichloromethane/MeOH) the title compound (0.26 g, 73%)as a yellow solid. MS (ISP) 296.0 [(M+H)⁺], mp 91° C.

Example B.23(RS)-1-(2-Amino-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol

a) To a stirred solution of (RS)-3-pyrrolidinol (0.51 g, 5.85 mmol) inTHF (12 ml) was added at 0° C. (ice water bath) commercially available2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.0 g, 3.93 mmol) andtriethylamine (0.6 ml, 4.32 mmol). The light yellow suspension wasstirred at room temperature for 17 h, and evaporated. The crude productwas further purified by flash chromatography on silica gel(dichloromethane/MeOH) and subsequent crystallization(dichloromethane/MeOH/hexane) to yield(RS)-1-(2-acetamido-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (0.82g, 68%) as a white solid. MS (ISP) 306.3 [(M+H)⁺]; mp 241° C.

b) A stirred suspension of(RS)-1-(2-acetamido-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (0.82g, 2.68 mmol) in 6N hydrochloric acid (13 ml) was heated for 2 h at 80°C. evaporated, and saturated NaHCO₃ solution (20 ml) was added. Themixture was extracted with ethyl acetate (3×50 ml), the combined organiclayers washed with brine (50 ml), dried (MgSO₄) and evaporated. Thecrude product was further purified by crystallization(dichloromethane/MeOH/hexane) to yield the title compound (0.62 g, 88%)as a white solid. MS (ISP) 263.8 [(M+H)⁺]; mp 165° C.

Synthesis of Intermediates Compounds Pyrazolo-pyrimidine CarboxylicAcids of Formula (VI) From Acetophenones

Some of the intermediates compounds, e.g. the pyrazolo-pyrimidinecarboxylic acids derivatives which can be used according to the generalprocedures I and II are commercially available. However some of saidintermediates have been prepared from acetophenones according to theprocedures as outlined hereafter and unless otherwise specified, thesecompounds are novel. The person skilled in the art will be able toprepare other pyrazolo-pyrimidine carboxylic acids derivatives useful inthe general procedures I and II taking into account the followingexamples of preparation:

Example C.17-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

a) To a stirred solution of ethyl difluoroacetate (5.0 ml, 21 mmol) intert-butyl-methyl-ether (30 ml) was added at room temperature a 5.4Msolution of sodium methanolate in methanol (4.65 ml, 25 mmol) followedby a solution of commercially available 4-trifluoromethyl-acetophenone(4.0 g, 21 mmol) in tert-butyl-methyl-ether (10 ml). The reactionmixture was stirred at room temperature for 19 h, poured into ice/water(50 ml), acidified with 2N HCl (40 ml) and extracted with diethyl ether(2×100 ml). The combined organic layers were washed with brine (2×50ml), dried (MgSO₄) and evaporated to give crude4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (5.87 g) as ayellow liquid, which was used without further purification.

b) A stirred mixture of commercially available3-amino-4-ethoxycarbonyl-pyrazole (3.38 g, 22 mmol) and4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (5.8 g, 22mmol) in acetic acid (45 ml) was heated under reflux conditions for 1.5h. The reaction mixture was evaporated and the crude product (yellowsolid, 8.5 g, 22 mmol) was dissolved in a mixture of 2M KOH in methanol(176.5 ml, 0.35 mol) and water (85 ml). The reaction mixture was stirredat 60° C. for 1.5 h, poured into ice/water (200 ml), acidified with 3Nsulfuric acid (pH=4) and stirred at room temperature for 30 min. Theprecipitate was collected by filtration and further purified bycrystallization from diethylether/methanol to give the title compound(4.51 g, 57%) as an off-white solid. MS (ISP) 356.1 [(M−H)⁻]; m.p. 261°C.

Example C.27-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyltrifluoroacetate, commercially available 4-trifluoromethyl-acetophenoneand commercially available 3-amino-4-ethoxycarbonyl-pyrazole accordingto the general procedure I.

Light yellow solid. MS (EI) 374.9 [M]; mp 248° C.

Example C.35-(4-Chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyldifluoroacetate, commercially available 4-chloro-acetophenone andcommercially available 3-amino-4-ethoxycarbonyl-pyrazole according tothe general procedure I. Off-white solid. MS (ISP) 322.2 [(M−H)⁻]; mp232° C.

Example C.45-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyltrifluoroacetate, commercially available 4-chloro-acetophenone andcommercially available 3-amino-4-ethoxycarbonyl-pyrazole according tothe general procedure I. Off-white solid. MS (ISP) 340.0 [(M−H)⁻]; mp238° C.

Example C.57-Difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyldifluoroacetate, 3-methyl-4-trifluoro-acetophenone (example A.4) andcommercially available 3-amino-4-ethoxycarbonyl-pyrazole according tothe general procedure I. Off-white solid. MS (ISP) 370.1 [(M−H)⁻]; mp217° C.

Example C.65-(4-Chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyltrifluoroacetate, commercially available 4-chloro-3-methyl-acetophenoneand commercially available 3-amino-4-ethoxycarbonyl-pyrazole accordingto the general procedure I. Off-white solid. MS (ISP) 354.0 [(M−H)⁻]; mp243° C.

Example C.75-(3,4-Dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyldifluoroacetate, commercially available 3,4-dichloro-acetophenone andcommercially available 3-amino-4-ethoxycarbonyl-pyrazole according tothe general procedure I. Off-white solid. MS (ISP) 356.0 [(M−H)⁻]; mp263° C.

Example C.85-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyltrifluoroacetate, 3-methyl-4-trifluoro-acetophenone (example A.4) andcommercially available 3-amino-4-ethoxycarbonyl-pyrazole according tothe general procedure I. Off-white solid. MS (ISP) 388.1 [(M−H)⁻]; mp250° C.

Example C.95-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyltrifluoroacetate, commercially available 3,4-dichloro-acetophenone andcommercially available 3-amino-4-ethoxycarbonyl-pyrazole according tothe general procedure I. Light yellow solid. MS (ISP) 374.1 [(M−H)⁻]; mp264° C.

Example C.105-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyltrifluoroacetate, 3-(2,2,2-trifluoroethoxy-4-trifluoro-acetophenone(Example A.6) and commercially available3-amino-4-ethoxycarbonyl-pyrazole according to the general procedure I.Off-white solid. MS (ISP) 471.9 [(M−H)⁻]; mp 264° C.

Example C.115-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyltrifluoroacetate, 3-ethoxy-4-trifluoro-acetophenone (Example A.5) andcommercially available 3-amino-4-ethoxycarbonyl-pyrazole according tothe general procedure I. Off-white solid. MS (ISP) 418.0 [(M−H)⁻]; mp264° C.

Example C.127-Difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyldifluoroacetate, 3-ethoxy-4-trifluoro-acetophenone (Example A.5) andcommercially available 3-amino-4-ethoxycarbonyl-pyrazole according tothe general procedure I. Yellow solid. MS (ISP) 400.2 [(M−H)⁻]; mp 247°C.

Example C.135-(4-Chloro-3-methyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyldifluoroacetate, commercially available 4-chloro-3-methyl-acetophenoneand commercially available 3-amino-4-ethoxycarbonyl-pyrazole accordingto the general procedure I. Light yellow solid. MS (ISP) 336.0 [(M−H)⁻];mp 238° C.

Example C.147-Difluoromethyl-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyldifluoroacetate, 3-(2,2,2-trifluoroethoxy-4-trifluoro-acetophenone(Example A.6) and commercially available3-amino-4-ethoxycarbonyl-pyrazole according to the general procedure I.Off-white solid. MS (ISP) 454.2 [(M−H)⁻]; mp 261° C.

Example C.155-(3-Chloro-4-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyldifluoroacetate, 3-chloro-4-trifluoromethyl-acetophenone [CAS-No.129322-80-1] and commercially available3-amino-4-ethoxycarbonyl-pyrazole according to the general procedure I.

Light red solid. MS (ISP) 390.2 [(M−H)⁻]; mp 216° C.

Example C.167-Difluoromethyl-5-(3-fluoro-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyldifluoroacetate, commercially available3-fluoro-4-trifluoromethyl-acetophenone and commercially available3-amino-4-ethoxycarbonyl-pyrazole according to the general procedure I.

Light brown solid. MS (ISP) 374.1 [(M−H)⁻]; mp 233° C.

Example C.175-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyltrifluoroacetate, 3-chloro-4-trifluoromethyl-acetophenone [CAS-No.129322-80-1] and commercially available3-amino-4-ethoxycarbonyl-pyrazole according to the general procedure I.

Light yellow solid. MS (ISP) 408.0 [(M−H)⁻]; mp 244° C.

Example C.185-(3-Fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

The title compound was prepared from commercially available ethyltrifluoroacetate, commercially available3-fluoro-4-trifluoromethyl-acetophenone and commercially available3-amino-4-ethoxycarbonyl-pyrazole according to the general procedure I.

Light yellow solid. MS (ISP) 392.0 [(M−H)⁻]; mp 212° C.

Example C.195-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid

a) A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (18.1 g,0.080 mol) and ethyl 5-amino-1H-pyrazole-4-carboxylate (13.7 g, 0.088mol) was stirred at 160° C. for 3 h. AcOEt (40 mL) and hexane (40 mL)were successively added to the cooled mixture and stirring was continuedat 0° C. for 0.5 h. The crystals were isolated by filtration and thesolid was triturated for 1.2 h with 0.2 N HCl (80 mL). The solid wasfiltered off, washed with water and dried to give ethyl5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate(13.3 g, 52%). White solid. MS (ISN) 316.3 [(M−H)⁻]; mp 190-192° C.

b) A mixture of5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate(9.53 g, 0.03 mol), phosphorous oxychloride (11.0 mL, 0.12 mol), andN,N-dimethylaniline (1.3 mL, 0.01 mol) was stirred for 2 h at 100° C.The mixture was evaporated in vacuo and the residue was partitionedbetween water and dichloromethane. The organic phase was washed withwater, dried (Na₂SO₄) and evaporated in vacuo. The remaining solid wascrystallized from AcOEt/hexane to give7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (6.80 g, 67%).Pale-yellow solid. MS (ISP) 336.0 [(M+H)⁺]; mp 133-135° C.

c) To a solution of7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (4.0 g, 12.0mmol), tetrakis(triphenylphosphin)palladium (1.15 g, 1.0 mmol) in THF(20 mL) was added at 20° C. 0.25 M cyclopropylzinc chloride/THFsuspension (ca.192 mL, 48 mmol; freshly prepared by stirring a mixtureof 96 mL of 0.5 M cyclopropylmagnesium bromide/THF and 96 mL of 0.5 Mzinc chloride/THF (96 mL) for 1 h at 0° C. followed by 1 h at 20° C.)and the mixture was refluxed in an atmosphere of argon for 2.5 h. Afterthe slow addition at 0° C. of sat. aqueous NH₄Cl solution (30 mL), themixture was partitioned between AcOEt and 10% sodium chloride solution.The organic layer was evaporated in vacuo and the residue waschromatographed on silica gel using AcOEt/cyclohexane (1:4 v/v) aseluent to give after crystallization from AcOEt the title compound (2.54g, 62%). Off-white solid. MS (ISP) 342.1 [(M+H)⁺]; mp 141-143° C.

d) A mixture of ethyl5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (0.95 g, 2.8 mmol) and 2 N NaOH solution (5.6 mL) in MeOH (35 mL)was heated to 80° C. for 0.5 h. The mixture was cooled, diluted withwater (150 mL) and washed with diethyl ether. The aqueous layer wasacidified by the addition of 3N HCl to pH 2. The precipitate formed wasisolated by filtration, washed with water, and dried to give the titlecompound (0.75 g, 86%). Off-white solid. MS (ISN) 312.3 [(M−H)⁻]; mp256° C.

Synthesis of the Compounds of the Invention Example 17-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic-acid(2-chloro-5-sulfamoyl-thiophen-3-yl)-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-chloro-thipohene-2-sulfonic acid amide(example B.1) according to general procedure II. Light brown solid. MS(ISP) 549.9 [(M−H)⁻]; mp 298° C.

Example 27-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 4-amino-5-chloro-thipohene-2-sulfonic acid amide(example B.1) according to general procedure II. Light brown solid. MS(ISP) 567.9 [(M+H)⁺]; mp 275° C.

Example 37-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5-sulfamoyl-[1,3,4]thiadiazol-2-yl)-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 5-amino-[1,3,4]thiadiazole-2-sulfonic acid amide[commercially available, CAS 14949-00-9] according to general procedureII.

Light yellow solid. MS (ISP) 518.0 [(M−H)⁻]; mp 284° C.

Example 47-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5-sulfamoyl-[1,3,4]thiadiazol-2-yl)-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 5-amino-[1,3,4]thiadiazole-2-sulfonic acid amide[commercially available, CAS 14949-00-9] according to general procedureII.

Light yellow solid. MS (ISP) 536.1 [(M−H)⁻]; mp 280° C.

Example 57-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to generalprocedure II. Light yellow solid. MS (ISP) 622.2 [(M−H)⁻]; mp 233° C.

Example 67-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to generalprocedure II. Light yellow solid. MS (ISP) 640.1 [ (M+H)⁺]; mp 223° C.

Example 77-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-4-methyl-thiazole-2-sulfonic acid amide[CAS-No. 187230-38-2] according to general procedure II. Light yellowsolid. MS (ISP) 531.0 [(M−H)⁻]; mp 284° C.

Example 87-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 2-amino-4-methyl-thiazole-2-sulfonic acid amide[CAS-No. 187230-38-2] according to general procedure II. Yellow solid.MS (ISP) 549.0 [(M−H)⁻]; mp 303° C.

Example 95-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide

The title compound was prepared from5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.4) and 4-amino-5-chloro-thipohene-2-sulfonic acid amide(example B.1) according to general procedure II. Yellow solid. MS (ISP)534.0 [(M−H)⁻]; mp 329° C.

Example 105-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide

The title compound was prepared from5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.10) 4-amino-5-chloro-thipohene-2-sulfonic acid amide(example B.1) according to general procedure II. Yellow solid. MS (ISP)612.2 [(M−H)⁻]; mp 281° C.

Example 115-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide

The title compound was prepared from5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.8) and 4-amino-5-chloro-thipohene-2-sulfonic acid amide(example B.1) according to general procedure II. Yellow solid. MS (ISP)581.8 [(M−H)⁻]; mp 283° C.

Example 125-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.4) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to generalprocedure II. Yellow solid. MS (ISP) 605.8 [(M−H)⁻]; mp 272° C.

Example 137-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II. Yellow solid. MS (ISP) 621.0 [(M−H)⁻]; mp 257° C.

Example 147-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II. Yellow solid. MS (ISP) 603.0 [(M−H)⁻]; mp 268° C.

Example 155-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to generalprocedure II. Yellow solid. MS (ISP) 684.3 [(M−H)⁻]; mp 234° C.

Example 165-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.8) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to generalprocedure II. Yellow solid. MS (ISP) 654.2 [(M−H)⁻]; mp 207° C.

Example 175-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to generalprocedure II.

Yellow solid. MS (ISP) 738.3 [(M−H⁻]; mp 264° C.

Example 185-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.17) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to generalprocedure II.

Yellow solid. MS (ISP) 674.3 [(M+H)⁺]; mp 254° C.

Example 195-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.4) and 2-amino-4-methyl-thiazole-2-sulfonic acid amide[CAS-No. 187230-38-2] according to general procedure II. Yellow solid.MS (ISP) 515.0 [(M−H)⁻]; mp 305° C.

Example 205-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.10) and 2-amino-4-methyl-thiazole-2-sulfonic acid amide[CAS-No. 187230-38-2] according to general procedure II. Yellow solid.MS (ISP) 595.4 [(M+H)⁺]; mp 300° C.

Example 215-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.8) and 2-amino-4-methyl-thiazole-2-sulfonic acid amide[CAS-No. 187230-38-2] according to general procedure II. Yellow solid.MS (ISP) 563.3 [(M−H)⁻]; mp 309° C.

Example 225-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.4) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II. Yellow solid. MS (ISP) 587.1 [(M+H)⁺]; mp 274° C.

Example 235-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.10) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II. Light yellow solid. MS (ISP) 665.2 [(M−H)⁻]; mp 276° C.

Example 245-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.8) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II. Yellow solid. MS (ISP) 635.0 [(M+H)⁺]; mp 272° C.

Example 255-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.17) and 2-amino-4-methyl-thiazole-2-sulfonic acid amide[CAS-No. 187230-38-2] according to general procedure II.

Light brown solid. MS (ISP) 585.1 [(M+H)⁺]; mp 299° C.

Example 265-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.9) and 2-amino-4-methyl-thiazole-2-sulfonic acid amide[CAS-No. 187230-38-2] according to general procedure II. Yellow solid.MS (ISP) 549.2 [(M−H)⁻]; mp 307° C.

Example 275-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.4) according togeneral procedure II. Yellow solid. MS (ISP) 649.1 [(M+H⁺]; mp 264° C.

Example 287-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.4) according togeneral procedure II. Light yellow solid. MS (ISP) 624.2 [(M−H)⁻]; mp241° C.

Example 297-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.4) according togeneral procedure II. Yellow solid. MS (ISP) 642.2 [(M−H)⁻]; mp 225° C.

Example 305-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.17) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II. Yellow solid. MS (ISP) 655.1 [(M−H)⁻]; mp 274° C.

Example 315-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.9) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II. Yellow solid. MS (ISP) 621.0 [(M−H)⁻]; mp 265° C.

Example 325-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.10) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II.

Yellow solid. MS (ISP) 719.3 [(M−H⁻]; mp 275° C.

Example 337-Difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.5) and 2-amino-4-methyl-thiazole-2-sulfonic acid amide[CAS-No. 187230-38-2] according to general procedure II. Yellow solid.MS (ISP) 545.1 [(M−H)⁻]; mp 307° C.

Example 347-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-2-chloro-thiophen-3-yl}-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acidbis-(2-hydroxy-ethyl)-amide (example B.5) according to general procedureII. Light yellow solid. MS (ISP) 640.3 [(M+H)⁺]; mp 216° C.

Example 357-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-2-chloro-thiophen-3-yl}-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acidbis-(2-hydroxy-ethyl)-amide (example B.5) according to general procedureII.

Yellow solid. MS (ISP) 658.4 [(M+H)⁺]; mp 217° C.

Example 367-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-ethyl)-amide (example B.6) according to general procedure II.Yellow solid. MS (ISP) 612.0 [(M−H)⁻]; mp 191° C.

Example 377-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.7) accordingto general procedure II. Light yellow solid. MS (ISP) 638.0 [(M−H)⁻]; mp237° C.

Example 387-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.7) accordingto general procedure II. Yellow solid. MS (ISP) 656.0 [(M−H)⁻]; mp 201°C.

Example 397-Difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.8) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II. Yellow solid. MS (ISP) 617.2 [(M−H)⁻]; mp 271° C.

Example 407-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-4-methyl-thiazol-2-yl}-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acidbis-(2-hydroxy-ethyl)-amide (example B.8) according to general procedureII. Light yellow solid. MS (ISP) 621.1 [(M+H)⁺]; mp 191° C.

Example 417-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-4-methyl-thiazol-2-yl}-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acidbis-(2-hydroxy-ethyl)-amide (example B.8) according to general procedureII.

Yellow solid. MS (ISP) 639.1 [(M+H)⁺]; mp 214° C.

Example 427-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.9) accordingto general procedure II. Yellow solid. MS (ISP) 637.0 [(M−H)⁻]; mp 250°C.

Example 437-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.9) accordingto general procedure II. Yellow solid. MS (ISP) 619.2 [(M−H)⁻]; mp 248°C.

Example 447-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-ethyl)-amide (example B.6) according to general procedure II.Yellow solid. MS (ISP) 594.1.2 [(M−H)⁻]; mp 209° C.

Example 457-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-hydroxy-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-ethyl)-amide (example B.10) according to general procedureII. Yellow solid. MS (ISP) 575.1 [(M−H)⁻]; mp 134° C.

Example 467-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-hydroxy-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-ethyl)-amide (example B.10) according to general procedureII. Yellow solid, MS (ISP) 593.1 [(M−H)⁻]; mp 166° C.

Example 477-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-methyl-5-sulfamoyl-thiophen-3-yl)-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-methyl-thiophene-2-sulfonic acid amide(example B.11 ) according to general procedure II. Yellow solid. MS(ISP) 548.1 [(M−H)⁻]; mp 297° C.

Example 487-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-methyl-5-sulfamoyl-thiophen-3-yl)-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-methyl-thiophene-2-sulfonic acid amide(example B.11) according to general procedure II. Yellow solid. MS (ISP)530.0 [(M−H)⁻]; mp 313° C.

Example 497-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-2-methyl-thiophen-3-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 4-amino-5-methyl-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.12) according to generalprocedure II. Yellow solid. MS (ISP) 620.3 [(M−H)⁻]; mp 225° C.

Example 507-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-2-methyl-thiophen-3-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-methyl-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.12) according to generalprocedure II. Yellow solid. MS (ISP) 602.2 [(M−H)⁻]; mp 180° C.

Example 517-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-thiazole-5-sulfonic acid amide [CAS-No.63735-95-5] according to general procedure II. Yellow solid. MS (ISP)535.2 [(M−H)⁻]; mp 309° C.

Example 527-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5-sulfamoyl-thiazol-2-yl)-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 2-amino-thiazole-5-sulfonic acid amide [CAS-No.63735-95-5] according to general procedure II. Light yellow solid. MS(ISP) 517.2 [(M−H)⁻]; mp 311° C.

Example 535-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.10) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.9) accordingto general procedure II. Light yellow solid. MS (ISP) 681.2 [(M−H)⁻]; mp220° C.

Example 547-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(2-dimethylamino-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-dimethylamino-ethyl)-amide (example B.14) according to generalprocedure II.

Yellow solid. MS (ISP) 623.1 [(M−H)⁻]; mp 162° C.

Example 557-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(2-dimethylamino-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-dimethylamino-ethyl)-amide (example B.14) according to generalprocedure II.

Yellow solid. MS (ISP) 639.1 [(M−H)⁻]; mp 198° C.

Example 565-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-ethyl)-amide (example B.6) according to general procedure II.Light yellow solid. MS (ISP) 656.0 [(M−H)⁻]; mp 250° C.

Example 577-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-dimethylamino-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-dimethylamino-ethyl)-amide (example B.15) according to generalprocedure II.

Yellow solid. MS (ISP) 602.1 [(M−H)⁻]; mp 217° C.

Example 587-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-dimethylamino-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-dimethylamino-ethyl)-amide (example B.15) according to generalprocedure II.

Yellow solid. MS (ISP) 620.2 [(M−H)⁻]; mp 235° C.

Example 597-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiazol-2-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 2-amino-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.13) according to generalprocedure II. Yellow solid. MS (ISP) 607.0 [(M−H)⁻]; mp 292° C.

Example 607-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiazol-2-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.13) according to generalprocedure II. Yellow solid. MS (ISP) 589.2 [(M−H)⁻]; mp 280° C.

Example 615-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide

The title compound was prepared from5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.19) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to generalprocedure II. Pale-yellow solid. (ISN) 580.0 [(M−H)⁻]; mp 238-241° C.

Example 625-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.19) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to generalprocedure II. Pale-yellow solid. MS (ISN) 559.0 [(M−H)⁻]; mp 293-294° C.

Example 637-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.16) according togeneral procedure II. Light yellow solid. MS (ISP) 604.8 [(M−H)⁻]; mp217° C.

Example 647-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B. 16) according togeneral procedure II. Light yellow solid. MS (ISP) 623.1 [(M−H)⁻]; mp215° C.

Example 657-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-amino-ethylsulfamoyl)-2-chloro-thiophen-3-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and[2-(4-amino-5-chloro-thiophene-2-sulfonylamino)-ethyl]-carbamic acidtert-butyl ester (example B.17) according to general procedure II andsubsequent removal of the protecting group with trifluoroacetic acid indichloromethane at 0° C. for 3 h. Orange solid. MS (ISP) 595.0 [(M+H)⁺];mp 150° C.

Example 667-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[(RS)-2-chloro-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-thiophen-3-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and(RS)-1-(4-amino-5-chloro-thiophene-2-sulfonyl)-pyrrolidin-3-ol (exampleB.18) according to general procedure II. Yellow solid. MS (ISP) 622.2[(M+H)⁺]; mp 274° C.

Example 677-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[(RS)-2-chloro-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-thiophen-3-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and(RS)-1-(4-amino-5-chloro-thiophene-2-sulfonyl)-pyrrolidin-3-ol-(exampleB.18) according to general procedure II. Yellow solid. MS (ISP) 640.2[(M+H)⁺]; mp 270° C.

Example 687-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine (exampleB.19) according to general procedure II.

Yellow solid. MS (ISP) 616.2 [(M+H)⁺]; mp 269° C.

Example 697-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine (exampleB.19) according to general procedure II. Yellow solid. MS (ISP) 634.1[(M+H)⁺]; mp 273° C.

Example 707-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid{5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-4-methyl-thiazol-2-yl}-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-ethyl)-methyl-amide (example B.20) according to generalprocedure II.

Light yellow solid. MS (ISP) 591.1 [(M+H)⁺]; mp 216° C.

Example 717-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid{5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-4-methyl-thiazol-2-yl}-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid(2-hydroxy-ethyl)-methyl-amide (example B.20) according to generalprocedure II.

Yellow solid. MS (ISP) 609.0 [(M+H)⁺]; mp 266° C.

Example 727-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid{2-chloro-5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-thiophen-3-yl}-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-ethyl)-methyl-amide (example B.21) according to generalprocedure II.

Light brown solid. MS (ISP) 607.8 [(M−H)⁻]; mp 231° C.

Example 737-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-ylamine (exampleB.22) according to general procedure II.

Yellow solid. MS (ISP) 635.3 [(M+H)⁺]; mp 293° C.

Example 747-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-ylamine (exampleB.22) according to general procedure II.

Yellow solid. MS (ISP) 653.3 [(M+H)⁺]; mp 301° C.

Example 75(RS)-7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[(RS)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-4-ethyl-thiazol-2-yl]-amide

The title compound was prepared from7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and(RS)-1-(2-amino-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (exampleB.23) according to general procedure II. Light yellow solid. MS (ISP)603.0 [(M+H)⁺]; mp 286° C.

Example 767-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[(RS)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-4-methyl-thiazol-2-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and(RS)-1-(2-amino-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (exampleB.23) according to general procedure II. Light yellow solid. MS (ISP)621.0 [(M+H)⁺]; mp 300° C.

Example 777-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid{2-chloro-5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-thiophen-3-yl}-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid(2-hydroxy-ethyl)-methyl-amide (example B.21) according to generalprocedure II.

Yellow solid. MS (ISP) 628.1 [(M+H)⁺]; mp 221° C.

Example 787-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-amino-ethylsulfamoyl)-2-chloro-thiophen-3-yl]-amide

The title compound was prepared from7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (example C.1) and[2-(4-amino-5-chloro-thiophene-2-sulfonylamino)-ethyl]-carbamic acidtert-butyl ester (example B.17) according to general procedure II andsubsequent removal of the protecting group with trifluoroacetic acid indichloromethane at 0° C. for 3 h. Yellow solid. MS (ISP) 611.0 [(M−H)⁻];mp 195° C.

Preparation of Pharmaceutical Compositions Comprising Compounds of theInvention:

Example I

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2Tablet weight 250

Example II

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 200 Powdered. lactose 100 White corn starch64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate4 Tablet weight 400

Example III

Capsules of the following composition are produced:

mg/Capsule Active ingredient 50 Crystalline. lactose 60 Microcrystallinecellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150

The active ingredient having a suitable particle size, the crystallinelactose and the microcrystalline cellulose are homogeneously mixed withone another, sieved and thereafter talc and magnesium stearate areadmixed. The final mixture is filled into hard gelatine capsules ofsuitable size.

1. A compound of formula (I)

wherein A is selected from the group consisting of:

R^(a) is H, halo or C₁₋₆-alkyl; R¹ is H, halo, C₁₋₆-alkoxy, C₁₋₆-alkyl,C₁₋₆-haloalkyl, or C₁₋₆-haloalkoxy; R² is halogen, or C₁₋₆-haloalkyl; R³is C₁₋₆-alkyl optionally substituted by hydroxy, or is NR^(b)R^(c)wherein R^(b) and R^(c) are independently selected from the groupconsisting of: H, C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5 to 12ring atoms, and C₁₋₆-alkyl which is optionally substituted by one ormore substituent(s) selected from the group consisting of halo, hydroxy,C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and—NR^(b′)R^(c′), wherein R^(b′) and R^(c′) are each independentlyselected from the group consisting of H and C₁₋₆-alkyl; or R^(b) andR^(c) can, together with the nitrogen atom to which they are attached,form an optionally substituted heterocyclic group having 5 to 12 ringatoms, wherein the substituents are selected from the group consistingof halo, hydroxy, C₁₋₆-alkyl and C₁₋₆-haloalkyl; and R⁴ is H, straightC₁₋₆-alkyl, C₁₋₆-haloalkyl or C₃₋₄-cycloalkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 wherein: A isselected from the group consisting of:

wherein R^(a) is H, halo or C₁₋₆-alkyl; R¹ is H, halo, C₁₋₆-alkoxy,C₁₋₆-alkyl, C₁₋₆-haloalkyl, or C₁₋₆-haloalkoxy; R² is halogen orC₁₋₆-haloalkyl; R³ is NR^(b)R^(c) wherein R^(b) and R^(c) are eachindependently selected from the group consisting of: H; C₁₋₆-allyl whichis optionally substituted by one or more substituent(s) selected fromthe group consisting of hydroxy and —NR^(b′)R^(c′), wherein R^(b′) andR^(c′) are each independently selected from the group consisting of Hand C₁₋₆-alkyl; and R⁴ is C₁₋₆-haloalkyl or C₃₋₄-cycloalkyl; or apharmaceutically acceptable salt thereof.
 3. The compound of claim 1,wherein A is selected from the group consisting of

R^(a) is H, Cl, or methyl; R¹ is H, Cl, MeO, EtO, methyl, CHF₂, CF₃, orCF₃CH₂O; R² is Cl, or CF₃; R³ is NR^(b)R^(c) wherein R^(b) and R^(c) areeach independently selected from the group consisting of H, methyl,ethyl, i-propyl, or t-butyl, each of which is optionally substituted byone or more substituent selected from the group consisting of hydroxyand —NR^(b′)R^(c′), wherein R^(b′) and R^(c′) are each independentlyselected from the group consisting of H and methyl; and R⁴ is CHF₂, CF₃,or cyclopropyl or a pharmaceutically acceptable salt thereof.
 4. Thecompound of claim 1, having formula (Ia):

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim4, selected from the group consisting of:7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-chloro-5-sulfamoyl-thiophen-3-yl)-amide;5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;and5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide.6. The compound of claim 4, selected from the group consisting of:5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;5-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;5-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic-acid{5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-2-chloro-thiophen-3-yl}-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-2-chloro-thiophen-3-yl}-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-amide; and7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-thiophen-3-yl]-amide.7. The compound of claim 4, selected from the group consisting of:7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-thiophen-3-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-methyl-5-sulfamoyl-thiophen-3-yl)-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2-methyl-5-sulfamoyl-thiophen-3-yl)-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-2-methyl-thiophen-3-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-2-methyl-thiophen-3-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[2-chloro-5-(2-dimethylamino-ethylsulfamoyl)-thiophen-3-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(2-dimethylamino-ethylsulfamoyl)-thiophen-3-yl]-amide;and5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-amide.
 8. Thecompound of claim 4, selected from the group consisting of:5-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[2-chloro-5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiophen-3-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-amino-ethylsulfamoyl)-2-chloro-thiophen-3-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[(R/S)-2-chloro-5-(3-hydroxy-pyrrolidinyl-1-sulfonyl)-thiophen-3-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[(R/S)-2-chloro-5-(3-hydroxy-pyrrolidinyl-1-sulfonyl)-thiophen-3-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid{2-chloro-5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-thiophen-3-yl}-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(4-methyl-piperzinyl-1-sulfonyl)-thiophen-3-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [2-chloro-5-(4-methyl-piperzinyl-1-sulfonyl)-thiophen-3-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid{2-chloro-5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-thiophen-3-yl}-amide;and7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-amino-ethylsulfamoyl)-2-chloro-thiophen-3-yl]-amide.
 9. Thecompound of claim 1, having formula (Ib):

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim9, selected from the group consisting of:7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5-sulfamoyl-[1,3,4]thiadiazol-2-yl)-amide; and7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5-sulfamoyl-[1,3,4]thiadiazol-2-yl)-amide.
 11. The compound ofclaim 1, having formula (Ic):

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim11, selected from the group consisting of:7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;and5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide.13. The compound of claim 11, selected from the group consisting of:5-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;5-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;5-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;5-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide;7-Difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;and7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-4-methyl-thiazol-2-yl}-amide.14. The compound of claim 11, selected from the group consisting of:7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid {5-[bis-(2-hydroxy-ethyl)-sulfamoyl]-4-methyl-thiazol-2-yl}-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-hydroxy-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5-sulfamoyl-thiazol-2-yl)-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5-sulfamoyl-thiazol-2-yl)-amide;5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-dimethylamino-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;and7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-dimethylamino-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide.15. The compound of claim 11, selected from the group consisting of:7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiazol-2-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-thiazol-2-yl]-amide;5-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1,1-dimethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[5-(2-hydroxy-1-hydroxymethyl-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [4-methyl-5-(4-methyl-piperzinyl-1-sulfonyl)-thiazol-2-yl]-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid [4-methyl-5-(4-methyl-piperzinyl-1-sulfonyl)-thiazol-2-yl]-amide;7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid{5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-4-methyl-thiazol-2-yl}-amide;7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid{5-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-4-methyl-thiazol-2-yl}-amide;(R/S)-7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[(R/S)-5-(3-hydroxy-pyrrolidinyl-1-sulfonyl)-4-methyl-thiazol-2-yl]-amide;and7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid[(R/S)-5-(3-hydroxy-pyrrolidinyl-1-sulfonyl)-4-methyl-thiazol-2-yl]-amide.16. The compound of claim 1, wherein R³ is C₁₋₆-alkyl optionallysubstituted by hydroxyl.
 17. The compound of claim 1, wherein R³ isNR^(b)R^(c) wherein R^(b) and R^(c) are independently selected from thegroup consisting of: H, C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5to 12 ring atoms, and C₁₋₆-alkyl which is optionally substituted by oneor more substituent(s) selected from the group consisting of halo,hydroxy, C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5 to 12 ringatoms and —NR^(b′)R^(c′), wherein R^(b′) and R^(c′) are eachindependently selected from the group consisting of H and C₁₋₆-alkyl; orR^(b) and R^(c) can, together with the nitrogen atom to which they areattached, form an optionally substituted heterocyclic group having 5 to12 ring atoms, wherein the substituents are selected from the groupconsisting of halo, hydroxy, C₁₋₆-alkyl and C₁₋₆-haloalkyl.
 18. Thecompound of claim 17, wherein R^(b) and R^(c) are hydrogen.
 19. Thecompound of claim 17, wherein R^(b) and R^(c) are each independentlyC₁₋₆-alkyl, optionally substituted by one or more substituent(s)selected from the group consisting of halo, hydroxy, andC₃₋₈-cycloalkyl.
 20. The compound of claim 17, wherein R^(b) and R^(c)are each independently C₁₋₆-alkyl, optionally substituted by—NR^(b′)R^(c′), wherein R^(b′) and R^(c′) are each independentlyselected from the group consisting of H and C₁₋₆-alkyl.
 21. The compoundof claim 17, wherein R^(b) and R^(c) together with the nitrogen atom towhich they are attached, form an optionally substituted heterocyclicgroup having 5 to 12 ring atoms, wherein the substituents are selectedfrom the group consisting of halo, hydroxy, C₁₋₆-alkyl andC₁₋₆-haloalkyl.
 22. A pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I)

wherein A is selected from the group consisting of:

R^(a) is H, halo or C₁₋₆-alkyl; R¹ is H, halo, C₁₋₆-alkoxy, C₁₋₆-alkyl,C₁₋₆-haloalkyl, or C₁₋₆-haloalkoxy; R² is halogen, or C₁₋₆-haloalkyl; R³is C₁₋₆-alkyl optionally substituted by hydroxy; or is NR^(b)R^(c)wherein R^(b) and R^(c) are independently selected from the groupconsisting of: H, C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5 to 12ring atoms, and C₁₋₆-alkyl which is optionally substituted by one ormore substituent(s) selected from the group consisting of halo, hydroxy,C₃₋₈-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms and—NR^(b′)R^(c′), wherein R^(b′) and R^(c′) are each independentlyselected from the group consisting of H and C₁₋₆-alkyl; or R^(b) andR^(c) can, together with the nitrogen atom to which they are attached,form an optionally substituted heterocyclic group having 5 to 12 ringatoms, wherein the substituents are selected from the group consistingof halo, hydroxy, C₁₋₆-alkyl and C₁₋₆-haloalkyl; and R⁴ is H, straightC₁₋₆-alkyl, C₁₋₆-haloalkyl or C₃₋₄-cycloalkyl; or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.